Crystalline forms of a 4-pyrimidinesulfamide derivative aprocitentan

ABSTRACT

The present invention concerns novel crystalline forms of {5-(4-bromo-phenyl)-6 [2 (5 bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide, processes for the preparation thereof, pharmaceutical compositions comprising said crystalline forms, pharmaceutical compositions prepared from such crystalline forms, and their use as endothelin receptor antagonists. It also relates to new uses of {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide, either alone or in combination with other active ingredients or therapeutic agents.

The present invention concerns novel crystalline forms of{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide(hereinafter also referred to as “COMPOUND”), processes for thepreparation thereof, pharmaceutical compositions comprising saidcrystalline forms, pharmaceutical compositions prepared from suchcrystalline forms, and their use as endothelin receptor inhibitors andendothelin receptor antagonists. It also relates to uses of the COMPOUNDfor treating particular diseases or disorders, either alone or incombination with other active ingredients or therapeutic agents.

Aprocitentan,{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamidehas the formula I

Aprocitentan, also known under the name ACT-132577, is an endothelinreceptor inhibitor and useful as endothelin receptor antagonist. Thecompound of formula I is a member of a structural family that waspreviously generically disclosed in WO 02/053557. In particular, thecompound of formula I, while showing endothelin receptor antagonistactivity, exhibits in vivo a much longer half-life and a much shorterclearance in comparison to corresponding alkylated derivatives. Thismakes the compound of formula I particularly suitable for long-actingpharmaceutical compositions, as disclosed in WO 2009/024906. Certainmanufacturing processes relating to aprocitentan are disclosed inWO2015/121397.

Because of its ability to inhibit the endothelin binding, COMPOUND canbe used for treatment of endothelin related diseases which areassociated with an increase in vasoconstriction, proliferation orinflammation due to endothelin. Examples of such endothelin relateddiseases are hypertension, pulmonary hypertension, coronary diseases,cardiac insufficiency, renal and myocardial ischemia, renal failure,cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage,Raynaud's syndrome, digital ulcers and portal hypertension. They canalso be used in the treatment or prevention of chronic kidney disease(CKD), diabetes, diabetic nephropathy, diabetic retinopathy, diabeticvasculopathy, chronic heart failure and diastolic dysfunction. they canfurther be used in the treatment or prevention of atherosclerosis,restenosis after balloon or stent angioplasty, inflammation, stomach andduodenal ulcer, cancer, melanoma, prostate cancer, prostatichypertrophy, erectile dysfunction, hearing loss, amaurosis, chronicbronchitis, asthma, pulmonary fibrosis, gram negative septicemia, shock,sickle cell anemia, glomerulonephritis, renal colic, glaucoma,connective tissue diseases, therapy and prophylaxis of diabeticcomplications, complications of vascular or cardiac surgery or afterorgan transplantation, complications of cyclosporin treatment, pain,hyperlipidemia as well as other diseases, presently known to be relatedto endothelin.

According to the 2014 American Society of Hypertension and InternationalSociety of Hypertension joint statement [Weber et al., “ClinicalPractice Guidelines for the Management of Hypertension in the Community.A Statement by the American Society of Hypertension and theInternational Society of Hypertension.” J Clin Hypertens (2014), 16(1),14-26], the 2013 European Society of Hypertension and European Societyof Cardiology joint guideline [Mancia et al, J. Hypertens. (2013), 31,1281 1357], as well as several national guidelines [Denolle et al., JHum Hypertens. (2016), 30(11), 657-663; McCormack et al., Br J Cardiol(2013), 20 (suppl 1), S1-S16], resistant hypertension (rHT) (ordifficult to treat hypertension) is defined as uncontrolled bloodpressure (BP) (i.e., failure to lower BP to a pre-defined threshold)despite concurrent administration of three antihypertensive therapies ofdifferent pharmacological classes at maximal or optimal doses, includinga diuretic. Thus, resistant hypertension patients include patients whoseblood pressure is controlled with use of more than three medications.That is, patients whose blood pressure is controlled but require four ormore medications to do so should be considered resistant to treatment(see e.g. Mancia et al, J. Hypertens. (2013)).

Clinical studies have shown that endothelin receptor antagonists (ERAs)may have significant treatment effect in patients suffering fromhypertension and/or renal disease. However, therapeutic benefit needs tobe weighted against potential side effects, such as the potential riskof teratogenic activity. In addition, both, selective ET_(A)-antagonistsand dual antagonists of both the ET_(A) and ET_(B) receptor, may causecause fluid retention, a common side effect associated with manypreviously studied ERAs and sometimes (e.g. if not manageable withdiuretics) leading to exaggerated major adverse cardiac events such asheart failure or death. Whereas the risk-benefit balance is in mostcases in favor of treatment with an ERA for indications such aspulmonary hypertension (as reflected in the past by successive marketapprovals e.g. for the ERAs the dual antagonists bosentan andmacitentan, the ET_(A)-selective antagonist ambrisentan), ERAs have norole in the management of primary hypertension (Laffin et al. Seminarsin Nephrology 2015, 35, 168-175), and side effects such as fluidretention may remain an issue when a potential treatment of rHT, chronickidney disease or other hypertension related diseases with an ERA isconsidered.

The ET_(A)-selective endothelin receptor antagonist darusentan has beenin development for the treatment of rHT (Bakris et al., Hypertension2010, 56,824-830, see also WO2007/098390). In a 14 week phase 3 trial inpatients with rHT, it demonstrated efficacy on the reduction ofambulatory blood pressure, but failed to show significant treatmenteffect on the primary endpoint systolic blood pressure. Patients wereeligible to participate if they had treatment resistant hypertension(systolic blood pressure of higher than 140 mm Hg) despite treatmentwith three or more antihypertensive drugs from different drug classes,including a diuretic, at optimized doses. A minimum dose of 25 mg perday of hydrochlorothiazide (or its equivalent for other thiazidediuretic drugs) was required. Even though during the trial diuretictherapy could be intensified at the discretion of the investigators tomanage fluid retention, the most frequent adverse event associated withdarusentan was fluid retention/edema at 28% versus 12% in each of theother groups. More patients withdrew because of adverse events ondarusentan as compared with placebo.

WO2016/073846 provides a comprehensive summary of ERAs tested forvarious indications including chronic kidney disease (CKD) and rHT.Similarly to the observations made for darusentan mentioned above, alsothe ET_(A)-selective ERA avosentan, in a trial that investigated the useof avosentan to reduce proteinuria in patients with diabetes, showedsignificant treatment effect, associated with a significantly increaseddiscontinuation of trial medications due to adverse events,predominantly related to fluid overload and congestive heart failure.The trial was terminated prematurely, and the authors conclude that “itmay be that at dosages of 25 to 50 mg, avosentan is less selective forthe ET_(A) receptor and thus caused sodium and water retention andperipheral vasodilation with a potential fluid shift from theintravascular to extravascular space. The assumption of ET_(B) receptorblockade with higher dosages of avosentan is further supported by datathat showed a natriuretic effect of selective ET_(A) receptor blockadein people who were treated with ACEIs (Mann et al., J Am Soc Nephrol.2010, 21(3): 527-535.” WO2016/073846 provides further examples wherefluid retention may have led to increased side effects for the ERAsbosentan, tezosentan, ambrisentan, and atrasentan. WO2016/073846concludes in proposing a method of treating CKD with an ERA, especiallywith the ET_(A)-selective ERA atrasentan, using predictors of fluidretention; said method comprising the determination of a risk of fluidretention if an ERA were administered to the subject; and administeringthe ERA to the subject if the risk is at an acceptable level.

Preclinical and clinical data suggest that the ET_(A)-selectiveantagonists sitaxentan and ambrisentan pose a greater risk of fluidretention than the dual ERAs bosentan and macitentan (Vercauteren etal., JPET 2017, 361, 322-333). On the other hand, pre-clinical datashowed that the synergistic effect on blood pressure of anET_(A)-selective ERA in combination with the ACE inhibitor enalapril wasabolished by simultaneous blockade of the ET_(B)-receptor (Goddard etal., J. Am. Soc. Nephrol. 2004, 15, 2601-2610). It has been shown in aphase 2 trial that aprocitentan, an ERA resulting in effective dualblockade of the endothelin receptors, may result in efficacious controlof blood pressure in subjects having essentialhypertension.(aprocitentan was administered as monotherapy, i.e. withoutbackground anti-hypertensive therapy) (Actelion Pharmaceuticals Ltd,press release May 22, 2017). Even though some indications of potentialfluid retention were observed (e.g. increased body weight at higherdoses, dose related decrease in the hemoglobin concentration, four casesof peripheral edema at higher doses), the overall frequency of adverseevents was similar to those observed in the placebo group. Thus,different from the methods of WO2016/073846 no risk assessment and/ordose reduction to mitigate side effects related to fluid retention maybe required for aprocitentan when used in the treatment of hypertensionrelated diseases, especially resistant hypertension. Thus, aprocitentanmay have a different pharmacological profile than the predominantlyETA-selective antagonists so far tested in resistant hypertension orchronic kidney disease in diabetic and non-diabetic patients.

It has now been found that certain crystalline forms of COMPOUND mayunder certain conditions be found. Said crystalline forms of COMPOUNDare novel and may have advantageous properties in view of the potentialuse of COMPOUND as active pharmaceutical ingredient. Such advantages mayinclude better flow properties; less hygroscopicity; betterreproducibility in manufacturing (for example better filtrationparameters, better reproducibility of formation, and/or bettersedimentation); and/or defined morphology. Such crystalline forms ofCOMPOUND may be particularly suitable in a process of manufacturingcertain pharmaceutical compositions. It has also been found thatCOMPOUND or a pharmaceutically acceptable salt thereof is particularlyuseful to treat certain disorders, in particular when used incombination with other active ingredients or therapeutic agents

DESCRIPTION OF THE FIGURES

FIG. 1 shows the X-ray powder diffraction diagram of COMPOUND in acrystalline form A, e.g. as obtained from Example 1. The X-raydiffraction diagram shows peaks having a relative intensity, as comparedto the most intense peak in the diagram, of the following percentages(relative peak intensities given in parenthesis) at the indicated anglesof refraction 2theta (selected peaks from the range 3-33° 2theta withrelative intensity larger then 10% are reported): 9.8° (18%), 9.9°(18%), 11.7° (14%), 14.5° (10%), 15.4° (14%), 15.6° (29%), 16.9° (19%),17.2° (16%), 17.8° (100%), 18.6° (50%), 19.9° (54%), 20.0° (67%), 21.5°(24%), 21.9° (10%), 22.8° (18%), 23.2° (49%), 23.5° (83%), 24.9° (32%),25.1° (20%), 25.3° (24%), 25.6° (33%), 25.9° (16%), 27.1° (23%), 27.3°(39%), 28.5° (13%), 29.0° (23%), 29.4° (15%), 30.1° (12%) and 30.6°(10%).

FIG. 2 shows the X-ray powder diffraction diagram of a dichloromethanesolvate of the COMPOUND in a crystalline form B, e.g. as obtained fromExample 2. The X-ray diffraction diagram shows peaks having a relativeintensity, as compared to the most intense peak in the diagram, of thefollowing percentages (relative peak intensitites given in parenthesis)at the indicated angles of refraction 2theta (selected peaks from therange 3-33° 2theta with relative intensity larger then 10% arereported): 11.2° (16%), 16.2° (57%), 18.0° (21%), 18.6° (71%), 18.8°(36%), 19.8° (19%), 20.3° (100%), 22.4° (45%), 22.9° (28%), 24.3° (44%),24.8° (11%), 25.0° (41%), 25.7° (22%), 26.1° (31%), 27.4° (20%), 29.4°(16%), 29.8° (38%) and 32.4° (12%).

FIG. 3 shows the X-ray powder diffraction diagram of COMPOUND in acrystalline form C, e.g. as obtained from Example 3. The X-raydiffraction diagram shows peaks having a relative intensity, as comparedto the most intense peak in the diagram, of the following percentages(relative peak intensitites given in parenthesis) at the indicatedangles of refraction 2theta (selected peaks from the range 3-33° 2thetawith relative intensity larger then 10% are reported): 7.8° (23%), 9.7°(42%), 15.7° (37%), 17.2° (16%), 17.8° (15%), 18.8° (26%), 19.8° (71%),20.1° (51%), 20.6° (15%), 21.6° (15%), 22.0° (100%), 23.4° (27%), 23.6°(40%), 24.1° (23%), 24.5° (16%), 25.1° (13%), 25.3° (39%), 25.7° (28%),26.8° (19%), 27.1° (16%), 28.5° (31%), 30.8° (13%) and 30.8° (13%).

FIG. 4 shows the X-ray powder diffraction diagram of COMPOUND in acrystalline form D, e.g. as obtained from Example 4. The X-raydiffraction diagram shows peaks having a relative intensity, as comparedto the most intense peak in the diagram, of the following percentages(relative peak intensitites given in parenthesis) at the indicatedangles of refraction 2theta (selected peaks from the range 3-33° 2thetawith relative intensity larger then 10% are reported): 4.6° (27%), 8.4°(15%), 8.6° (11%), 16.4° (17%), 16.8° (26%), 17.2° (10%), 18.6° (11%),18.9° (18%), 19.3° (40%), 19.6° (45%), 20.1° (100%), 20.6° (55%), 20.8°(26%), 22.0° (10%), 22.7° (14%), 23.0° (24%), 23.5° (32%), 23.8° (12%),24.2° (17%), 24.7° (20%), 25.1° (55%), 25.4° (22%), 25.6° (14%), 26.2°(16%), 26.8° (17%), 27.2° (28%), 28.1° (21%) and 28.1° (19%).

FIG. 5 shows the X-ray powder diffraction diagram of an acetonitrilesolvate of the COMPOUND in a crystalline form E, e.g. as obtained fromExample 5. The X-ray diffraction diagram shows peaks having a relativeintensity, as compared to the most intense peak in the diagram, of thefollowing percentages (relative peak intensitites given in parenthesis)at the indicated angles of refraction 2theta (selected peaks from therange 3-33° 2theta with relative intensity larger then 10% arereported): 9.0° (21%), 9.5° (56%), 11.3° (61%), 14.5° (41%), 14.8°(15%), 15.6° (47%), 16.0° (26%), 16.5° (100%), 18.2° (84%), 18.7° (73%),18.9° (56%), 20.2° (20%), 20.7° (56%), 22.8° (96%), 23.9° (22%), 24.5°(70%), 25.3° (77%), 25.6° (29%), 26.0° (14%), 26.6° (66%), 27.5° (27%),29.6° (31%), 30.2° (66%) and 33.0° (13%).

FIG. 6 shows the X-ray powder diffraction diagram of COMPOUND in acrystalline form J, e.g. as obtained from Example 6. The X-raydiffraction diagram shows peaks having a relative intensity, as comparedto the most intense peak in the diagram, of the following percentages(relative peak intensitites given in parenthesis) at the indicatedangles of refraction 2theta (selected peaks from the range 3-33° 2thetawith relative intensity larger then 10% are reported): 4.0° (44%), 4.7°(14%), 6.5° (23%), 9.0° (27%), 16.1° (40%), 17.2° (11%), 18.7° (22%),19.0° (58%), 19.4° (28%), 19.8° (46%), 20.7° (57%), 21.2° (17%), 21.9°(100%), 22.6° (14%), 23.2° (23%), 24.1° (37%), 24.8° (40%), 25.6° (42%),27.0° (29%), 28.2° (27%), 29.0° (20%), 30.3° and 30.8° (10%).

FIG. 7 shows the X-ray powder diffraction diagram of a dimethylsulfoxidesolvate of the COMPOUND in a crystalline form K, e.g. as obtained fromExample 7. The X-ray diffraction diagram shows peaks having a relativeintensity, as compared to the most intense peak in the diagram, of thefollowing percentages (relative peak intensitites given in parenthesis)at the indicated angles of refraction 2theta (selected peaks from therange 3-33° 2theta with relative intensity larger then 10% arereported): 10.9° (16%), 16.9° (18%), 18.2° (26%), 18.4° (30%), 18.6°(29%), 18.7° (55%), 19.3° (100%), 20.8° (35%), 21.2° (47%), 21.9° (26%),24.3° (21%), 24.8° (24%), 25.4° (29%), 25.8° (22%), 26.7° (34%), 27.7°(13%), 27.8° (14%), 28.6° (15%), 29.4° (18%), 31.5° (23%) and 31.8°(12%).

FIG. 8 shows the X-ray powder diffraction diagram of an ethanol solvateof the COMPOUND in a crystalline form L, e.g. as obtained from Example8. The X-ray diffraction diagram shows peaks having a relativeintensity, as compared to the most intense peak in the diagram, of thefollowing percentages (relative peak intensitites given in parenthesis)at the indicated angles of refraction 2theta (selected peaks from therange 3-33° 2theta with relative intensity larger then 10% arereported): 9.1° (31%), 9.3° (34%), 11.3° (49%), 12.2° (10%), 14.6°(17%), 14.8° (46%), 15.7° (16%), 16.1° (10%), 16.4° (80%), 17.9° (17%),18.2° (19%), 18.7° (96%), 20.0° (38%), 20.3° (100%), 22.6° (11%), 22.8°(76%), 23.2° (50%), 24.1° (14%), 24.5° (56%), 24.7° (68%), 25.4° (46%),25.9° (32%), 26.4° (14%), 26.8° (22%), 27.7° (38%), 28.2° (12%), 29.7°(11%), 29.5° (64%), 29.8° (14%), 30.3° (14%), 30.5° (13%) and 32.4°(16%).

For avoidance of any doubt, the above-listed peaks describe theexperimental results of the X-ray powder diffraction shown in FIG. 1 toFIG. 8. It is understood that, in contrast to the above peak list, onlya selection of characteristic peaks is required to fully andunambiguously characterize of the COMPOUND in the respective crystallineform of the present invention.

In the X-ray diffraction diagrams of FIG. 1 to FIG. 8 the angle ofrefraction 2theta 2θ) is plotted on the horizontal axis and the countson the vertical axis.

FIG. 9 shows the acute effects of COMPOUND on mean arterial bloodpressure

(“MAP”) in conscious, male hypertensive Dahl salt sensitive rats.

FIG. 10 shows the acute effects of COMPOUND on MAP in conscious, malehypertensive deoxycorticosterone acetate salt rats.

FIG. 11 shows the acute effects of COMPOUND on MAP in conscious, malespontaneaously hypertensive rats.

FIG. 12 shows the acute effects of COMPOUND, used alone or incombination with valsartan, on MAP in conscious, male spontaneaouslyhypertensive rats.

FIG. 13 shows the acute effects of COMPOUND, used alone or incombination with valsartan, on MAP in conscious, male hypertensivedeoxycorticosterone acetate salt rats.

FIG. 14 shows the acute effects of COMPOUND, used alone or incombination with enalapril, on MAP in conscious, male spontaneaouslyhypertensive rats.

FIG. 15 shows the acute effects of COMPOUND, used alone or incombination with amlodipine, on MAP in conscious, male hypertensivedeoxycorticosterone acetate salt rats.

FIG. 16 shows the effects of chronic oral administration of COMPOUND onMAP in conscious, male hypertensive deoxycorticosterone acetate saltrats.

FIG. 17 shows the effects of chronic oral administration of COMPOUND onrenal vascular resistance in conscious, male hypertensivedeoxycorticosterone acetate salt rats.

FIG. 18 shows the effects of a single dose oral administration ofCOMPOUND on haematocrit (Hct) male Wistar rats.

FIG. 19 shows the gravimetric vapour sorption diagram of COMPOUND in acrystalline form A as obtained from Example 1.

FIG. 20 shows the gravimetric vapour sorption diagram of COMPOUND in acrystalline form C as obtained from Example 3.

DETAILED DESCRIPTION OF THE INVENTION

1) A first embodiment of the invention relates to crystalline forms ofthe COMPOUND{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamideor of a solvate of that compound, characterized by:

-   -   form A of the COMPOUND comprising the presence of peaks in the        X-ray powder diffraction diagram at the following angles of        refraction 2θ: 17.8°, 20.0°, and 23.5°; or    -   form C of the COMPOUND comprising the presence of peaks in the        X-ray powder diffraction diagram at the following angles of        refraction 2θ: 9.7°, 15.7°, and 22.0°; or    -   form D of the COMPOUND comprising the presence of peaks in the        X-ray powder diffraction diagram at the following angles of        refraction 2θ: 4.6°, 16.8°, and 20.1°; or    -   form E of an acetonitrile solvate of the COMPOUND comprising the        presence of peaks in the X-ray powder diffraction diagram at the        following angles of refraction 2θ: 9.5°, 16.5°, and 18.2°; or    -   form J of the COMPOUND comprising the presence of peaks in the        X-ray powder diffraction diagram at the following angles of        refraction 2θ: 4.0°, 16.1°, and 21.9°; or    -   form K of a dimethylsulfoxide solvate of the COMPOUND comprising        the presence of peaks in the X-ray powder diffraction diagram at        the following angles of refraction 2θ: 16.9°, 19.3°, and 24.8°;        or    -   form L of an ethanol solvate of the COMPOUND comprising the        presence of peaks in the X-ray powder diffraction diagram at the        following angles of refraction 2θ: 11.3°, 16.4°, and 20.3°;

wherein said X-ray powder diffraction diagram is obtained by usingcombined Cu Kα1 and Kα2 radiation, without Kα2 stripping; and theaccuracy of the 2θ values is in the range of 2θ+/−0.2°.

It is understood, that the crystalline forms according to embodiment 1)comprise the COMPOUND in a crystalline form of the free base (i.e. notin form of a salt). Furthermore, said crystalline forms may comprisenon-coordinated and/or coordinated solvent. Coordinated solvent is usedherein as term for a crystalline solvate. Likewise, non-coordinatedsolvent is used herein as term for physiosorbed or physically entrappedsolvent (definitions according to Polymorphism in the PharmaceuticalIndustry (Ed. R. Hilfiker, VCH, 2006), Chapter 8: U.J. Griesser: TheImportance of Solvates). Crystalline forms A and C are anhydrate oransolvate forms i.e. they comprise no coordinated water, but maycomprise non-coordinated solvent such as isopropanol, methanol, ethanoland/or water, crystalline form B is a DCM solvate, crystalline form E isa MeCN solvate, crystalline form K is a DMSO solvate, and crystallineform L is an ethanol solvate.

It is to be understood that the present invention covers each of theforms A, C, D, E, J, K and L individually, as well as two, three, four,five, six or seven individual forms. Preferred are forms A and/or C,especially form A.

2) Another embodiment relates to a crystalline form of the COMPOUND orof a solvate of that compound, characterized by

-   -   form A of the COMPOUND comprising the presence of peaks in the        X-ray powder diffraction diagram at the following angles of        refraction 2θ: 17.8°, 18.6°, 20.0°, 23.2° and 23.5°; or    -   form C of the COMPOUND comprising the presence of peaks in the        X-ray powder diffraction diagram at the following angles of        refraction 2θ: 7.8°, 9.7°, 15.7°, 19.8° and 22.0°; or    -   form D of the COMPOUND comprising the presence of peaks in the        X-ray powder diffraction diagram at the following angles of        refraction 2θ: 4.6°, 16.8°, 19.6°, 20.1° and 20.6°; or    -   form E of an acetonitrile solvate of the COMPOUND comprising the        presence of peaks in the X-ray powder diffraction diagram at the        following angles of refraction 2θ: 9.5°, 15.6°, 16.5°, 18.2° and        26.6°; or    -   form J of the COMPOUND comprising the presence of peaks in the        X-ray powder diffraction diagram at the following angles of        refraction 2θ: 4.0°, 16.1°, 19.0°, 20.7° and 21.9°; or    -   form K of a dimethylsulfoxide solvate of the COMPOUND comprising        the presence of peaks in the X-ray powder diffraction diagram at        the following angles of refraction 2θ: 16.9°, 19.3°, 20.8°,        21.2° and 24.8°; or    -   form L of an ethanol solvate of the COMPOUND comprising the        presence of peaks in the X-ray powder diffraction diagram at the        following angles of refraction 2θ: 9.3°, 11.3°, 16.4°, 20.0° and        20.3°;

wherein said X-ray powder diffraction diagram is obtained by usingcombined Cu Kα1 and Kα2 radiation, without Kα2 stripping; and theaccuracy of the 2θ values is in the range of 2θ+/−0.2°. Preferred areforms A and/or C, especially form A.

3) Another embodiment relates to a crystalline form of the COMPOUND orof a solvate of that compound, characterized by:

-   -   form A of the COMPOUND comprising the presence of peaks in the        X-ray powder diffraction diagram at the following angles of        refraction 2θ: 9.8°, 9.9°, 11.7°, 17.8°, 18.6°, 20.0°, 21.5°,        22.8°, 23.2° and 23.5°; or    -   form C of the COMPOUND comprising the presence of peaks in the        X-ray powder diffraction diagram at the following angles of        refraction 2θ: 7.8°, 9.7°, 15.7°, 17.2°, 17.8°, 18.8°, 19.8°,        22.0°, 23.6°, and 25.3°; or    -   form D of the COMPOUND comprising the presence of peaks in the        X-ray powder diffraction diagram at the following angles of        refraction 2θ: 4.6°, 16.4°, 16.8°, 19.3°, 19.6°, 20.1°, 20.6°,        23.0°, 23.5°, and 25.1°; or    -   form E of an acetonitrile solvate of the COMPOUND comprising the        presence of peaks in the X-ray powder diffraction diagram at the        following angles of refraction 2θ: 9.5°, 15.6°, 16.0°, 16.5°,        18.2°, 18.7°, 25.3°, 26.6°, 29.6°, and 30.2°; or    -   form J of the COMPOUND comprising the presence of peaks in the        X-ray powder diffraction diagram at the following angles of        refraction 2θ: 4.0°, 6.5°, 9.0°, 16.1°, 19.0°, 19.8°, 20.7°,        21.9°, 24.1°, and 24.8°; or    -   form K of a dimethylsulfoxide solvate of the COMPOUND comprising        the presence of peaks in the X-ray powder diffraction diagram at        the following angles of refraction 2θ: 10.9°, 13.7°, 16.9°,        18.2°, 19.3°, 20.8°, 21.2°, 24.3°, 24.8°, and 26.7°; or    -   form L of an ethanol solvate of the COMPOUND comprising the        presence of peaks in the X-ray powder diffraction diagram at the        following angles of refraction 2θ: 9.1°, 9.3°, 11.3°, 14.8°,        16.4°, 20.0°, 20.3°, 22.8°, 24.5°, and 24.7°;

wherein said X-ray powder diffraction diagram is obtained by usingcombined Cu Kα1 and Kα2 radiation, without Kα2 stripping; and theaccuracy of the 2θ values is in the range of 2θ+/−0.2°. Preferred areforms A and/or C, especially form A.

4) Another embodiment relates to a crystalline form of the COMPOUND orof a solvate thereof, characterized by:

-   -   form A of the COMPOUND comprising the presence of peaks in the        X-ray powder diffraction diagram at the following angles of        refraction 2θ: 9.8°, 9.9°, 11.7°, 14.5°, 15.4°, 15.6°, 16.9°,        17.2°, 17.8°, 18.6°, 19.9°, 20.0°, 21.5°, 21.9°, 22.8°, 23.2°,        23.5°, 24.9°, 25.1°, 25.3°, 25.6°, 25.9°, 27.1°, 27.3°, 28.5°,        29.0°, 29.4°, 30.1° and 30.6°; or    -   form C of the COMPOUND comprising the presence of peaks in the        X-ray powder diffraction diagram at the following angles of        refraction 2θ: 7.8°, 9.7°, 15.7°, 17.2°, 17.8°, 18.8°, 19.8°,        20.1°, 20.6°, 21.6°, 22.0°, 23.4°, 23.6°, 24.1°, 24.5°, 25.1°,        25.3°, 25.7°, 26.8°, 27.1°, 28.5°, 30.8° and 30.8°; or    -   form D of the COMPOUND comprising the presence of peaks in the        X-ray powder diffraction diagram at the following angles of        refraction 2θ: 4.6°, 8.4°, 8.6°, 16.4°, 16.8°, 17.2°, 18.6°,        18.9°, 19.3°, 19.6°, 20.1°, 20.6°, 20.8°, 22.0°, 22.7°, 23.0°,        23.5°, 23.8°, 24.2°, 24.7°, 25.1°, 25.4°, 25.6°, 26.2°, 26.8°,        27.2°, 28.1° and 28.1°; or    -   form E of an acetonitrile solvate of the COMPOUND comprising the        presence of peaks in the X-ray powder diffraction diagram at the        following angles of refraction 2θ: 9.0°, 9.5°, 11.3°, 14.5°,        14.8°, 15.6°, 16.0°, 16.5°, 18.2°, 18.7°, 18.9°, 20.2°, 20.7°,        22.8°, 23.9°, 24.5°, 25.3°, 25.6°, 26.0°, 26.6°, 27.5°, 29.6°,        30.2° and 33.0°; or    -   form J of the COMPOUND comprising the presence of peaks in the        X-ray powder diffraction diagram at the following angles of        refraction 2θ: 4.0°, 4.8°, 6.5°, 9.0°, 16.1°, 17.2°, 18.7°,        19.0°, 19.4°, 19.8°, 20.7°, 21.2°, 21.9°, 22.6°, 23.2°, 24.1°,        24.8°, 25.6°, 27.0°, 28.2°, 29.0°, 30.4° and 30.8°; or    -   form K of a dimethylsulfoxide solvate of the COMPOUND comprising        the presence of peaks in the X-ray powder diffraction diagram at        the following angles of refraction 2θ: 10.9°, 16.9°, 18.2°,        18.4°, 18.6°, 18.7°, 19.3°, 20.8°, 21.2°, 21.9°, 24.3°, 24.8°,        25.4°, 25.8°, 26.7°, 27.7°, 27.8°, 28.6°, 29.4°, 31.5° and        31.8°; or    -   form L of an ethanol solvate of the COMPOUND comprising the        presence of peaks in the X-ray powder diffraction diagram at the        following angles of refraction 2θ: 9.1°, 9.3°, 11.3°, 12.2°,        14.6°, 14.8°, 15.7°, 16.1°, 16.4°, 17.9°, 18.2°, 18.7°, 20.0°,        20.3°, 22.6°, 22.8°, 23.2°, 24.1°, 24.5°, 24.7°, 25.5°, 25.9°,        26.4°, 26.8°, 27.7°, 28.2°, 29.7°, 29.5°, 29.8°, 30.3°, 30.5°        and 32.4°;

wherein said X-ray powder diffraction diagram is obtained by usingcombined Cu Kα1 and Kα2 radiation, without Kα2 stripping; and theaccuracy of the 2θ values is in the range of 2θ+/−0.2°. Preferred areforms A and/or C, especially form A.

5) Another embodiment relates to a crystalline form of the COMPOUND orof a solvate thereof; characterized by:

-   -   form A of the COMPOUND comprising the presence of peaks in the        X-ray powder diffraction diagram at the following angles of        refraction 2θ: 9.8° (18%), 9.9° (18%), 11.7° (14%), 14.5° (10%),        15.4° (14%), 15.6° (29%), 16.9° (19%), 17.2° (16%), 17.8°        (100%), 18.6° (50%), 19.9° (54%), 20.0° (67%), 21.5° (24%),        21.9° (10%), 22.8° (18%), 23.2° (49%), 23.5° (83%), 24.9° (32%),        25.1° (20%), 25.3° (24%), 25.6° (33%), 25.9° (16%), 27.1° (23%),        27.3° (39%), 28.5° (13%), 29.0° (23%), 29.4° (15%), 30.1° (12%)        and 30.6° (10%); or    -   form C of the COMPOUND comprising the presence of peaks in the        X-ray powder diffraction diagram at the following angles of        refraction 2θ: 7.8° (23%), 9.7° (42%), 15.7° (37%), 17.2° (16%),        17.8° (15%), 18.8° (26%), 19.8° (71%), 20.1° (51%), 20.6° (15%),        21.6° (15%), 22.0° (100%), 23.4° (27%), 23.6° (40%), 24.1°        (23%), 24.5° (16%), 25.1° (13%), 25.3° (39%), 25.7° (28%), 26.8°        (19%), 27.1° (16%), 28.5° (31%), 30.8° (13%) and 30.8° (13%); or    -   form D of the COMPOUND comprising the presence of peaks in the        X-ray powder diffraction diagram at the following angles of        refraction 2θ: 4.6° (27%), 8.4° (15%), 8.6° (11%), 16.4° (17%),        16.8° (26%), 17.2° (10%), 18.6° (11%), 18.9° (18%), 19.3° (40%),        19.6° (45%), 20.1° (100%), 20.6° (55%), 20.8° (26%), 22.0°        (10%), 22.7° (14%), 23.0° (24%), 23.5° (32%), 23.8° (12%), 24.2°        (17%), 24.7° (20%), 25.1° (55%), 25.4° (22%), 25.6° (14%), 26.2°        (16%), 26.8° (17%), 27.2° (28%), 28.1° (21%) and 28.1° (19%); or    -   form E of an acetonitrile solvate of the COMPOUND comprising the        presence of peaks in the X-ray powder diffraction diagram at the        following angles of refraction 2θ: 9.0° (21%), 9.5° (56%), 11.3°        (61%), 14.5° (41%), 14.8° (15%), 15.6° (47%), 16.0° (26%), 16.5°        (100%), 18.2° (84%), 18.7° (73%), 18.9° (56%), 20.2° (20%),        20.7° (56%), 22.8° (96%), 23.9° (22%), 24.5° (70%), 25.3° (77%),        25.6° (29%), 26.0° (14%), 26.6° (66%), 27.5° (27%), 29.6° (31%),        30.2° (66%) and 33.0° (13%); or    -   form J of the COMPOUND comprising the presence of peaks in the        X-ray powder diffraction diagram at the following angles of        refraction 2θ: 4.0° (44%), 4.8° (14%), 6.5° (23%), 9.0° (27%),        16.1° (40%), 17.2° (11%), 18.7° (22%), 19.0° (58%), 19.4° (28%),        19.8° (46%), 20.7° (57%), 21.2° (17%), 21.9° (100%), 22.6°        (14%), 23.2° (23%), 24.1° (37%), 24.8° (40%), 25.6° (42%), 27.0°        (29%), 28.2° (27%), 29.0° (20%), 30.4° and 30.8° (10%); or    -   form K of a dimethylsulfoxide solvate of the COMPOUND comprising        the presence of peaks in the X-ray powder diffraction diagram at        the following angles of refraction 2θ: 10.9° (16%), 16.9° (18%),        18.2° (26%), 18.4° (30%), 18.6° (29%), 18.7° (55%), 19.3°        (100%), 20.8° (35%), 21.2° (47%), 21.9° (26%), 24.3° (21%),        24.8° (24%), 25.4° (29%), 25.8° (22%), 26.7° (34%), 27.7° (13%),        27.8° (14%), 28.6° (15%), 29.4° (18%), 31.5° (23%) and 31.8°        (12%); or    -   form L of an ethanol solvate of the COMPOUND comprising the        presence of peaks in the X-ray powder diffraction diagram at the        following angles of refraction 2θ: 9.1° (31%), 9.3° (34%), 11.3°        (49%), 12.2° (10%), 14.6° (17%), 14.8° (46%), 15.7° (16%), 16.1°        (10%), 16.4° (80%), 17.9° (17%), 18.2° (19%), 18.7° (96%), 20.0°        (38%), 20.3° (100%), 22.6° (11%), 22.8° (76%), 23.2° (50%),        24.1° (14%), 24.5° (56%), 24.7° (68%), 25.5° (46%), 25.9° (32%),        26.4° (14%), 26.8° (22%), 27.7° (38%), 28.2° (12%), 29.7° (11%),        29.5° (64%), 29.8° (14%), 30.3° (14%), 30.5° (13%) and 32.4°        (16%);

wherein said X-ray powder diffraction diagram is obtained by usingcombined Cu Kα1 and Kα2 radiation, without Kα2 stripping; and theaccuracy of the 2θ values is in the range of 2θ+/−0.2°. Preferred areforms A and C, especially form A.

The present data show peaks having a relative intensity, as compared tothe most intense peak in the diagram, of the following percentages(relative peak intensitites given in parentheses) at the indicatedangles of refraction 2theta (selected peaks from the range 3-33° 2thetawith relative intensity larger then 10% are reported).

6) Another embodiment relates to a crystalline form of the COMPOUND orof a solvate thereof which essentially shows the X-ray powderdiffraction pattern as depicted in any one of the FIGS. 1, 3, 4, 5, 6, 7and 8, wherein said X-ray powder diffraction diagram is obtained byusing combined Cu Kα1 and Kα2 radiation, without Kα2 stripping; and theaccuracy of the 2θ values is in the range of 2θ+/−0.2°.

In this context the term “essentially” means that at least the majorpeaks of the diagram depicted in said figures, i.e. those having arelative intensity of more than 10%, especially more than 20%, ascompared to the most intense peak in the diagram, have to be present.

However, the person skilled in the art of X-ray powder diffraction willrecognize that relative intensities in X-ray powder diffraction diagramsmay be subject to strong intensity variations due to preferredorientation effects.

7) A particular sub-embodiment of embodiment 6) relates to a crystallineform of COMPOUND which essentially shows the X-ray powder diffractionpattern as depicted in FIG. 1, wherein said X-ray powder diffractiondiagram is obtained by using combined Cu Kα1 and Kα2 radiation, withoutKα2 stripping; and the accuracy of the 2θ values is in the range of2θ+/−0.2°.

8) In another embodiment the present invention relates to a crystallineform of the COMPOUND or of a solvate thereof wherein

-   -   (a) form A is obtainable by crystallisation of the COMPOUND in        an aqueous solution at pH 6.2 to 6.8;    -   (b) form B is obtainable by crystallisation of the COMPOUND from        DCM at pH 7;    -   (c) form C is obtainable by crystallisation of the COMPOUND from        MeOH, EtOH or propan-2-ol;    -   (d) form D is obtainable by crystallisation of form A from        methyl-ethylketone;    -   (e) form E is obtainable by crystallisation of form A from MeCN;    -   (j) form J is obtainable by crystallisation of form B from DMSO        and water;    -   (k) form K is obtainable by crystallisation of the COMPOUND in        an aqueous solution;    -   (l) form L is obtainable by crystallisation of form K from EtOH.

9) Another embodiment of the present invention relates to a crystallineform A of the COMPOUND comprising the presence of peaks in the X-raypowder diffraction diagram at the following angles of refraction 2θ:17.8°, 20.0°, and 23.5°; whereby it is an anhydrate or ansolvate form.It is understood that the X-ray powder diffraction diagram may furthercomprise the peaks as disclosed in embodiment 2), 3), 4), 5) or 6). Itis further understood that said crystalline form may be furthercharacterized by an endothermic event with a peak of the endothermobserved at about 159° C. as determined by DSC, e.g. using the methoddisclosed in the experimental part.

10) Another embodiment of the present invention relates to a crystallineform A of the COMPOUND comprising the presence of peaks in the X-raypowder diffraction diagram at the following angles of refraction 2θ:17.8°, 20.0°, and 23.5°; whereby it is an anhydrate or ansolvate formwhich is obtainable by crystallisation in an aqueous solution at pH 6.2to 6.8. It is understood that the X-ray powder diffraction diagram mayfurther comprise the peaks as disclosed in embodiment 2), 3), 4), 5) or6).

11) Another embodiment of the present invention relates to a crystallineform B of a dichloromethane solvate of the COMPOUND comprising thepresence of peaks in the X-ray powder diffraction diagram at thefollowing angles of refraction 2θ: 16.2°, 18.6°, and 20.3° (notably16.2°, 18.6°, 20.3°, 22.4° and 24.3°, especially 9.0°, 11.2°, 16.2°,18.0°, 18.6°, 19.8°, 20.3°, 22.4°, 22.9° and 24.3°).

12) Another embodiment of the present invention relates to a crystallineform B of a dichloromethane solvate of the COMPOUND comprising thepresence of peaks in the X-ray powder diffraction diagram at thefollowing angles of refraction 2θ: 16.2°, 18.6°, and 20.3° (notably16.2°, 18.6°, 20.3°, 22.4° and 24.3°, especially 9.0°, 11.2°, 16.2°,18.0°, 18.6°, 19.8°, 20.3°, 22.4°, 22.9° and 24.3°); whereby this formis obtainable by crystallisation from dichloromethane at pH 7.

13) Another embodiment of the present invention relates to a crystallineform C of the COMPOUND comprising the presence of peaks in the X-raypowder diffraction diagram at the following angles of refraction 2θ:9.7°, 15.7°, and 22.0°; whereby it is an anhydrate or ansolvate form. Itis understood that the X-ray powder diffraction diagram may furthercomprise the peaks as disclosed in embodiment 2), 3), 4), 5) or 6). Itis further understood that said crystalline form may be furthercharacterized by an endothermic event with a peak of the endothermobserved at about 153° C. as determined by DSC, e.g. using the methoddisclosed in the experimental part.

14) Another embodiment of the present invention relates to a crystallineform C of the COMPOUND comprising the presence of peaks in the X-raypowder diffraction diagram at the following angles of refraction 2θ:9.7°, 15.7°, and 22.0°; whereby it is an anhydrate or ansolvate formwhich is obtainable by crystallisation MeOH, EtOH or propan-2-ol. It isunderstood that the X-ray powder diffraction diagram may furthercomprise the peaks as disclosed in embodiment 2), 3), 4), 5) or 6).

15) Another embodiment of the present invention relates to a crystallineform D of the COMPOUND comprising the presence of peaks in the X-raypowder diffraction diagram at the following angles of refraction 2θ:4.6°, 16.8°, and 20.1°; whereby it is obtainable by crystallisation ofform A from methyl-ethylketone. It is understood that the X-ray powderdiffraction diagram may further comprise the peaks as disclosed inembodiment 2), 3), 4), 5) or 6).

16) Another embodiment of the present invention relates to a crystallineform E of an acetonitrile solvate of the COMPOUND comprising thepresence of peaks in the X-ray powder diffraction diagram at thefollowing angles of refraction 2θ: 9.5°, 16.5°, and 18.2°. It isunderstood that the X-ray powder diffraction diagram may furthercomprise the peaks as disclosed in embodiment 2), 3), 4), 5) or 6).

17) Another embodiment of the present invention relates to a crystallineform E of an acetonitrile solvate of the COMPOUND comprising thepresence of peaks in the X-ray powder diffraction diagram at thefollowing angles of refraction 2θ: 9.5°, 16.5°, and 18.2°; whereby thisform is obtainable by crystallisation of form A from acetonitrile. It isunderstood that the X-ray powder diffraction diagram may furthercomprise the peaks as disclosed in embodiment 2), 3), 4), 5) or 6).

18) Another embodiment of the present invention relates to a crystallineform J of the COMPOUND comprising the presence of peaks in the X-raypowder diffraction diagram at the following angles of refraction 2θ:4.0°, 16.1°, and 21.9°; whereby it is obtainable by crystallisation ofform B of a dichloromethane solvate of the COMPOUND from DMSO and water.It is understood that the X-ray powder diffraction diagram may furthercomprise the peaks as disclosed in embodiment 2), 3), 4), 5) or 6).

19) Another embodiment of the present invention relates to a crystallineform K of a dimethylsulfoxide solvate of the COMPOUND comprising thepresence of peaks in the X-ray powder diffraction diagram at thefollowing angles of refraction 2θ: 16.9°, 19.3°, and 24.8°. It isunderstood that the X-ray powder diffraction diagram may furthercomprise the peaks as disclosed in embodiment 2), 3), 4), 5) or 6).

20) Another embodiment of the present invention relates to a crystallineform K of a dimethylsulfoxide solvate of the COMPOUND comprising thepresence of peaks in the X-ray powder diffraction diagram at thefollowing angles of refraction 2θ: 16.9°, 19.3°, and 24.8°; whereby thisform is obtainable by crystallisation in an aqueous solution. It isunderstood that the X-ray powder diffraction diagram may furthercomprise the peaks as disclosed in embodiment 2), 3), 4), 5) or 6).

21) Another embodiment of the present invention relates to a crystallineform L of an ethanol solvate of the COMPOUND comprising the presence ofpeaks in the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 11.3°, 16.4°, and 20.3°; whereby it is obtainable bycrystallisation of form K from ethanol. It is understood that the X-raypowder diffraction diagram may further comprise the peaks as disclosedin embodiment 2), 3), 4), 5) or 6).

For avoidance of any doubt, whenever one of the above embodiments refersto “peaks in the X-ray powder diffraction diagram at the followingangles of refraction 20”, said X-ray powder diffraction diagram isobtained by using combined Cu Kα1 and Kα2 radiation, without Kα2stripping; and it should be understood that the accuracy of the 2θvalues as provided herein is in the range of +/−0.1-0.2°. Notably, whenspecifying an angle of refraction 2theta (2θ) for a peak in theinvention embodiments and the claims, the 2θ value given is to beunderstood as an interval from said value minus 0.2° to said value plus0.2° (2θ+/−0.2°); and preferably from said value minus 0.1° to saidvalue plus 0.1° (2θ+/−0.1°).

When defining the presence of peak in e.g. an X-ray powder diffractiondiagram, a common approach is to do this in terms of diagram depicted(S=signal, N=noise). According to this definition, when stating that apeak has to be present in an X-ray powder diffraction diagram, it isunderstood that the peak in the X-ray powder diffraction diagram isdefined by having an S/N ratio (S=signal, N=noise) of greater than x (xbeing a numerical value greater than 1), usually greater than 2,especially greater than 3.

Unless used regarding temperatures, the term “about” placed before anumerical value “X” refers in the current application to an intervalextending from X minus 10% of X to X plus 10% of X, and preferably to aninterval extending from X minus 5% of X to X plus 5% of X. In theparticular case of temperatures, the term “about” placed before atemperature “Y” refers in the current application to an intervalextending from the temperature Y minus 10° C. to Y plus 10° C.,preferably to an interval extending from Y minus 5° C. to Y plus 5° C.,notably to an interval extending from Y minus 3° C. to Y plus 3° C. Roomtemperature means a temperature of about 25° C. When in the currentapplication the term n equivalent(s) is used wherein n is a number, itis meant and within the scope of the current application that n isreferring to about the number n, preferably n is referring to the exactnumber n.

Whenever the word “between” or “to” is used to describe a numericalrange, it is to be understood that the end points of the indicated rangeare explicitly included in the range.

For example: if a temperature range is described to be between 40° C.and 80° C. (or 40° C. to 80° C.), this means that the end points 40° C.and 80° C. are included in the range; or if a variable is defined asbeing an integer between 1 and 4 (or 1 to 4), this means that thevariable is the integer 1, 2, 3, or 4.

22) Another embodiment of the present invention relates to an amorphousform of the COMPOUND{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide.Thus, the amorphous form may be obtained by milling form A. For Example,the amorphous form is obtainable by milling in a ball mill (MM200 RetschBall Mill, 2 agate beads), 30 min at 30 Hz at ambient temperature.

23) The crystalline forms, especially the essentially pure crystallineforms, of the COMPOUND according to any one of embodiments 1) to 21) canbe used as medicaments, e.g. in the form of pharmaceutical compositionsfor enteral or parenteral administration.

The term “essentially pure” is understood in the context of the presentinvention to mean especially that at least 90, preferably at least 95,and most preferably at least 99 percent by weight of COMPOUND is presentin the respective crystalline form.

24) Another embodiment thus relates to a crystalline form of COMPOUNDaccording to any one of embodiments 1) to 21) for use as a medicament.

The crystalline solid, especially the essentially pure crystallinesolid, of COMPOUND according to any one of embodiments 1) to 21) may beused as single component or as mixtures with other crystalline forms orthe amorphous form of COMPOUND.

The production of the pharmaceutical compositions can be effected in amanner which will be familiar to any person skilled in the art (see forexample Remington, The Science and Practice of Pharmacy, 21st Edition(2005), Part 5, “Pharmaceutical Manufacturing” [published by LippincottWilliams & Wilkins]) by bringing the crystalline forms of the presentinvention, optionally in combination with other therapeutically valuablesubstances, into a galenical administration form together with suitable,non-toxic, inert, pharmaceutically acceptable solid or liquid carriermaterials and, if desired, usual pharmaceutical adjuvants.

25) Another embodiment of the present invention relates to a crystallineform of the COMPOUND or of a solvate of that compound, according to anyone of embodiments 1) to 21), for the use in the manufacture of apharmaceutical composition, wherein said pharmaceutical compositioncomprises as active ingredient the compound{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide,and at least one therapeutically inert excipient.

Such pharmaceutical compositions according to embodiment 25) areespecially useful for the treatment of hypertension, pulmonaryhypertension, coronary diseases, cardiac insufficiency, renal andmyocardial ischemia, renal failure, cerebral ischemia, dementia,migraine, subarachnoidal hemorrhage, Raynaud's syndrome, digital ulcersor portal hypertension as well as for the treatment or prevention ofatherosclerosis, restenosis after balloon or stent angioplasty,inflammation, stomach and duodenal ulcer, cancer, melanoma, prostatecancer, prostatic hypertrophy, erectile dysfunction, hearing loss,amaurosis, chronic bronchitis, asthma, pulmonary fibrosis, gram negativesepticemia, shock, sickle cell anemia, glomerulonephritis, renal colic,glaucoma, connective tissue diseases, diabetic complications,complications of vascular or cardiac surgery or after organtransplantation, complications of cyclosporin treatment, pain orhyperlipidemia. The pharmaceutical compositions according to embodiment25) are also useful for the treatment of Chronic Kidney Disease (CKD),especially CKD of stages 1 to 4 as defined by the Kidney DiseaseImproving Global Outcomes (KDIGO) Guidelines (and notably CKD of stage3), and in particular CKD (notably of these stages) caused by essentialhypertension.

Preferably, they are useful for in the treatment of a disease selectedfrom the group consisting of hypertension, pulmonary hypertension,diabetic arteriopathy, heart failure, erectile dysfunction, anginapectoris and CKD [especially CKD of stages 1 to 4 as defined by theKidney Disease Improving Global Outcomes (KDIGO) Guidelines (and notablyCKD of stage 3); and in particular CKD (notably of these stages) causedby essential hypertension].

Moreover, they are useful in the treatment of a disease selected fromthe group consisting of essential hypertension, resistant hypertension,pulmonary hypertension and pulmonary arterial hypertension (and notablyin the treatment of resistant hypertension).

Essential hypertension (also called primary hypertension or idiopathichypertension) is the form of hypertension that by definition has noidentifiable cause. It represents a significant global public healthconcern, contributing to vascular and renal morbidity and tocardiovascular mortality. The diagnosis of essential hypertension ismade when the average of multiple systolic blood pressure measurementson 2 or more subsequent visits is consistently equal to or above acertain threshold value T_(SBP). Individuals with high normal bloodpressure tend to maintain pressures that are above average for thegeneral population and are at greater risk for development of definitehypertension and cardiovascular events than the general population. Thethreshold value T_(SBP) above which treatment is recommended isregularly discussed among clinicians (see e.g. Mancia et al, J.Hypertens. (2013), 31, 1281-1357); accordingly, depending on thepatient's general condition and age, T_(SBP) could be 140 or 130 mm Hg,or another suitable value.

The term “resistant hypertension” in the present invention is defined asblood pressure that remains above goal in spite of the concurrent use of3 antihypertensive agents of different classes. One of the 3 agentsshould be a diuretic and all agents should be prescribed atoptimal/maximal dose amounts. As defined, resistant hypertensionpatients include patients whose blood pressure is controlled with use ofmore than 3 medications. That is, patients whose blood pressure iscontrolled but require 4 or more medications to do so should beconsidered resistant to treatment (see e.g. Mancia et al, J. Hypertens.(2013), 31, 1281-1357).

“Diuretic” in particular means in the present application a diuretic ofthe thiazide class (a thiazide-like diuretic) such as especiallychlorthalidone, hydrochlorothiazide, chlorothiazide, indapamide, ormetolazone. Preferred diuretics are chlorthalidone orhydrochlorothiazide.

The invention, thus, further relates to COMPOUND, especially acrystalline form of COMPOUND according to any one of embodiments 1) to21) (in particular crystalline Form A or C), wherein COMPOUND/saidcrystalline form is used as a medicament, especially for the treatmentof resistant hypertension; wherein COMPOUND/said crystalline form isused alone or (preferably) in combination (preferably for simultaneouslyadministration, including a fixed dose combination) with a diuretic, inparticular hydrochlorothiazide (HCTZ or HCT). In a sub-embodiment, saidcombination of COMPOUND/said crystalline form according to any one ofembodiments 1) to 21) (in particular crystalline Form A or C) with adiuretic, in particular hydrochlorothiazide (HCTZ or HCT) for thetreatment of resistant hypertension; may require further combination(preferably for simultaneously administration, including a fixed dosecombination) with one or two additional active ingredients that areantihypertensive agents of different classes (especially a CCB and/or anARB), in particular valsartan. The invention, thus, especially relatesto pharmaceutical compositions comprising COMPOUND/the respectivecrystalline form of COMPOUND as defined in any one of embodiments 26) to31) below; comprising as active ingredients, in addition to COMPOUND/therespective crystalline form of COMPOUND, a diuretic, in particularhydrochlorothiazide (HCTZ or HCT); and optionally further comprising oneor two active ingredients that are antihypertensive agents of differentclasses (especially a CCB and/or an ARB); in particular furthercomprising valsartan.

26) Another embodiment of the present invention relates to apharmaceutical composition comprising as active ingredient a crystallineform of the COMPOUND according to any one of embodiments 1) to 21), andat least one therapeutically inert excipient.

27) The invention thus also relates to a solid pharmaceuticalcomposition (in particular in the form of a tablet) comprising COMPOUND,especially a crystalline form of the COMPOUND according to any one ofembodiments 1) to 21) (especially solid form A of the COMPOUND, asdescribed in any one of embodiments 1) to 7)), microcrystallinecellulose, lactose, hydroxypropylcellulose, croscarmellose sodium andmagnesium stearate; it will in particular relate to a solidpharmaceutical composition (in particular in the form of a tablet)consisting of a crystalline form of the COMPOUND according to any one ofembodiments 1) to 21) (especially solid form A thereof, as described inany one of embodiments 1) to 7)), microcrystalline cellulose, lactose,hydroxypropylcellulose, croscarmellose sodium and magnesium stearate.

28) Preferably, the solid pharmaceutical composition of embodiment 27)will comprise COMPOUND, especially the crystalline form of the COMPOUNDaccording to any one of embodiments 1) to 21) (especially solid form Aof the COMPOUND, as described in any one of embodiments 1) to 7)) in atotal amount from 1 to 25% (especially 5 to 25%) in weight based on thetotal weight of the pharmaceutical composition, microcrystallinecellulose in a total amount from 20 to 35% (especially 20 to 30%) inweight based on the total weight of the pharmaceutical composition,lactose in a total amount from 40 to 65% in weight based on the totalweight of the pharmaceutical composition, hydroxypropylcellulose in atotal amount from 1 to 3% in weight based on the total weight of thepharmaceutical composition, croscarmellose sodium in a total amount from2 to 8% in weight based on the total weight of the pharmaceuticalcomposition and magnesium stearate in a total amount from 0.2 to 2% inweight based on the total weight of the pharmaceutical composition,whereby the total percent in weight of the solid pharmaceuticalcomposition will always be 100; the aforementioned solid pharmaceuticalcomposition will particularly be in the form of a tablet.

Such pharmaceutical compositions according to any of embodiments 26) to28) are especially useful for the treatment of endothelin relateddiseases and disorders, notably the diseases and disorders of embodiment25).

29) A further embodiment of the invention relates to a pharmaceuticalcomposition according to any one of embodiments 26) to 28), wherein saidpharmaceutical composition is in form of a tablet.

30) In particular, the pharmaceutical composition of embodiment 29) willbe in the form of a tablet consisting of the solid form A of theCOMPOUND (as described in any one of embodiments 1) to 7)) in a totalamount from 1 to 25% (especially 5 to 25%) in weight based on the totalweight of the pharmaceutical composition, microcrystalline cellulose ina total amount from 20 to 35% (especially 20 to 30%) in weight based onthe total weight of the pharmaceutical composition, lactose in a totalamount from 40 to 65% in weight based on the total weight of thepharmaceutical composition, hydroxypropylcellulose in a total amountfrom 1 to 3% in weight based on the total weight of the pharmaceuticalcomposition, croscarmellose sodium in a total amount from 2 to 8% inweight based on the total weight of the pharmaceutical composition andmagnesium stearate in a total amount from 0.2 to 2% in weight based onthe total weight of the pharmaceutical composition, whereby the totalpercent in weight of the solid pharmaceutical composition will always be100.

A tablet according to embodiment 29) or 30) can optionally be coatedwith a suitable protective pellicle. Said protective pellicle willnotably prevent direct contact of the pharmaceutical composition withmoisture; it may also ease imprints that may be desired to be used inorder to distinguish the pharmaceutical composition from others.

The coating material for making such protective pellicle may include alow water vapour permeability polymer (such as a polyvinyl alcohol (e.g.Aquapolish® white PVA from manufacturer Biogrund) or dimethylaminoethylmethacrylate (e.g. EUDRAGIT® E PO)). The coating material can furtherinclude a plasticizing agent (e.g. propylene glycol, triacetyne, dibutylphthalate or dibutyl sebacate), a surfactant (e.g. sodium laurylsulphate or a polysorbate such as Tween®) and/or a lubricant/glidant(e.g. stearic acid, magnesium or calcium stearate or talc). Moreover,the coating material can also include a pigment (e.g. iron(II) oxide,iron(III) oxide or titanium oxide) to give the tablet a coloured aspect.

31) A further embodiment of the invention relates to a pharmaceuticalcomposition according to any one of embodiments 26) to 28), wherein saidpharmaceutical composition is in form of a capsule.

For avoidance of any doubt, embodiments 25), 26), 27), 28), 29), 30) or31) especially refer to the crystalline forms according to any one ofembodiments 1) to 21) which is suitable/which is used as final isolationstep of COMPOUND (e.g. in order to meet the purity requirements ofpharmaceutical production), whereas the final pharmaceutical compositionaccording to embodiment 25), 26), 27), 28), 29), 30) or 31) may or maynot contain said crystalline form (e.g. because the originallycrystalline form of COMPOUND is further transformed during themanufacturing process and/or is dissolved in the pharmaceuticallyacceptable carrier material(s); thus, in the final pharmaceuticalcomposition, COMPOUND may be present in non-crystalline form, in anothercrystalline form, or in dissolved form, or the like).

32) A further embodiment of the invention relates to COMPOUND or apharmaceutically acceptable salt thereof, especially a crystalline formof COMPOUND according to any one of embodiments 1) to 21), for use inthe treatment of hypertension, pulmonary hypertension, coronarydiseases, cardiac insufficiency, renal and myocardial ischemia, renalfailure, cerebral ischemia, dementia, migraine, subarachnoidalhemorrhage,

Raynaud's syndrome, digital ulcers or portal hypertension as well as forthe treatment or prevention of atherosclerosis, restenosis after balloonor stent angioplasty, inflammation, stomach and duodenal ulcer, cancer,melanoma, prostate cancer, prostatic hypertrophy, erectile dysfunction,hearing loss, amaurosis, chronic bronchitis, asthma, pulmonary fibrosis,gram negative septicemia, shock, sickle cell anemia, glomerulonephritis,renal colic, glaucoma, connective tissue diseases, diabeticcomplications, complications of vascular or cardiac surgery or afterorgan transplantation, complications of cyclosporin treatment, pain,hyperlipidemia or CKD [especially CKD of stages 1 to 4 as defined by theKidney Disease Improving Global Outcomes (KDIGO) Guidelines (and notablyCKD of stage 3), and in particular CKD (notably of these stages) causedby essential hypertension].

33) A further embodiment of the invention relates to COMPOUND or apharmaceutically acceptable salt thereof, especially a crystalline formof COMPOUND according to any one of embodiments 1) to 21), for use inthe treatment of a disease selected from the group consisting ofhypertension, pulmonary hypertension, diabetic arteriopathy, heartfailure, erectile dysfunction, angina pectoris and CKD [especially CKDof stages 1 to 4 as defined by the Kidney Disease Improving GlobalOutcomes (KDIGO) Guidelines (and notably CKD of stage 3), and inparticular CKD (notably of these stages) caused by essentialhypertension].

34) A further embodiment of the invention relates to COMPOUND or apharmaceutically acceptable salt thereof, especially a crystalline formof COMPOUND according to any one of embodiments 1) to 21), for use inthe treatment of a disease selected from the group consisting ofessential hypertension, resistant hypertension, pulmonary hypertensionand pulmonary arterial hypertension (and notably for use in thetreatment of resistant hypertension).

For avoidance of any doubt, if a certain crystalline form of COMPOUND isdescribed as useful for the prevention/prophylaxis or treatment ofcertain diseases, such compounds are likewise suitable for use in thepreparation of a medicament for the prevention/prophylaxis or treatmentof said diseases. Likewise, such compounds are also suitable in a methodfor the prevention/prophylaxis or treatment of such diseases, comprisingadministering to a subject (mammal, especially human) in need thereof,an effective amount of such compound.

35) A further embodiment of the invention relates to the use of COMPOUNDor a pharmaceutically acceptable salt thereof, especially of acrystalline form of COMPOUND according to any one of embodiments 1) to21), for the preparation of a medicament intended for the treatment ofany one of the diseases or disorders mentioned in embodiment 32).

36) A further embodiment of the invention relates to the use of COMPOUNDor a pharmaceutically acceptable salt thereof, especially of acrystalline form of COMPOUND according to any one of embodiments 1) to21), for the preparation of a medicament intended for the treatment ofany one of the diseases or disorders mentioned in embodiment 33).

37) A further embodiment of the invention relates to the use of COMPOUNDor a pharmaceutically acceptable salt thereof, especially of acrystalline form of COMPOUND according to any one of embodiments 1) to21), for the preparation of a medicament intended for the treatment ofany one of the diseases or disorders mentioned in embodiment 34).

38) A further embodiment of the invention relates to a method for thetreatment of any one of the diseases or disorders mentioned inembodiment 32), comprising administering to a patient an effectiveamount of COMPOUND or a pharmaceutically acceptable salt thereof,especially of a crystalline form of COMPOUND according to any one ofembodiments 1) to 21), or of a pharmaceutical composition according toany one of embodiments 26) to 31).

39) A further embodiment of the invention relates to a method for thetreatment of any one of the diseases or disorders mentioned inembodiment 33), comprising administering to a patient an effectiveamount of COMPOUND or a pharmaceutically acceptable salt thereof,especially of a crystalline form of COMPOUND according to any one ofembodiments 1) to 21), or of a pharmaceutical composition according toany one of embodiments 26) to 31).

40) A further embodiment of the invention relates to a method for thetreatment of any one of the diseases or disorders mentioned inembodiment 34), comprising administering to a patient an effectiveamount of COMPOUND or a pharmaceutically acceptable salt thereof,especially of a crystalline form of COMPOUND according to any one ofembodiments 1) to 21), or of a pharmaceutical composition according toembodiments 26) to 31).

41) Yet another embodiment of the invention relates to the COMPOUND or apharmaceutically acceptable salt thereof, especially a crystalline formof COMPOUND according to any one of embodiments 1) to 21), for use inthe treatment of a disorder selected from the group consisting ofchronic kidney disease (CKD), diabetes, diabetic nephropathy, diabeticretinopathy, diabetic vasculopathy, chronic heart failure and diastolicdysfunction.

42) One sub-embodiment of embodiment 41) relates to the COMPOUND or apharmaceutically acceptable salt thereof, especially a crystalline formof COMPOUND according to any one of embodiments 1) to 21), for use inthe treatment of CKD, especially CKD of stages 1 to 4 as defined by theKidney Disease Improving Global Outcomes (KDIGO) Guidelines (and notablyCKD of stage 3), and in particular CKD (notably of these stages) causedby essential hypertension.

43) Another sub-embodiment of embodiment 41) relates to the COMPOUND ora pharmaceutically acceptable salt thereof, especially a crystallineform of COMPOUND according to any one of embodiments 1) to 21), for usein the treatment of diabetes (that is, type 1 or type 2 diabetes).

44) Another sub-embodiment of embodiment 41) relates to the COMPOUND ora pharmaceutically acceptable salt thereof, especially a crystallineform of COMPOUND according to any one of embodiments 1) to 21), for usein the treatment of diabetic nephropathy.

45) Another sub-embodiment of embodiment 41) relates to the COMPOUND ora pharmaceutically acceptable salt thereof, especially a crystallineform of COMPOUND according to any one of embodiments 1) to 21), for usein the treatment of diabetic retinopathy.

46) Another sub-embodiment of embodiment 41) relates to the COMPOUND ora pharmaceutically acceptable salt thereof, especially a crystallineform of COMPOUND according to any one of embodiments 1) to 21), for usein the treatment of diabetic vasculopathy.

47) Another sub-embodiment of embodiment 41) relates to the COMPOUND ora pharmaceutically acceptable salt thereof, especially a crystallineform of COMPOUND according to any one of embodiments 1) to 21), for usein the treatment of chronic heart failure.

48) According to one variant of sub-embodiment 47), the chronic heartfailure of sub-embodiment 47) will be heart failure with preservedejection fraction.

49) According to another variant of sub-embodiment 47), the chronicheart failure of sub-embodiment 47) will be diastolic heart failure.

50) Another sub-embodiment of embodiment 41) relates to the COMPOUND ora pharmaceutically acceptable salt thereof, especially a crystallineform of COMPOUND according to any one of embodiments 1) to 21), for usein the treatment of diastolic dysfunction.

51) Preferably, the COMPOUND or a pharmaceutically acceptable saltthereof [especially a crystalline form of COMPOUND according to any oneof embodiments 1) to 21)] according to any one of embodiments 41) to 50)will be comprised in a pharmaceutical unit dosage form suitable for theoral administration of 2.5 to 100 mg (in particular 5 or 10 to 50 mg,notably 25 or 50 mg) per day of the COMPOUND{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamideor of a pharmaceutically acceptable salt thereof.

52) Preferably, the COMPOUND or pharmaceutically acceptable salt thereof[especially a crystalline form of COMPOUND according to any one ofembodiments 1) to 21)] according to any one of embodiments 41) to 51)will be for use in combination with an Angiotensin Converting Enzyme(ACE) inhibitor, an Angiotensin Receptor Blocker (ARB) or a CalciumChannel Blocker (CCB), or with a pharmaceutically acceptable salt of oneof these.

“Angiotensin Converting Enzyme inhibitor” or “ACE inhibitor” inparticular means in the present application captopril, enalapril,ramipril, quinapril, perindopril, lisinopril, imidapril or cilazapril,or a pharmaceutically acceptable salt of one of these. A preferred ACEinhibitor is enalapril or a pharmaceutically acceptable salt thereof.

“Angiotensin Receptor Blocker” or “ARB” in particular means in thepresent application valsartan, losartan, telmisartan, irbesartan,candesartan, olmesartan, azilsartan, or a pharmaceutically acceptablesalt of one of these. A preferred ARB is valsartan or a pharmaceuticallyacceptable salt thereof.

“Calcium Channel Blocker” or “CCB” in particular means in the presentapplication amlodipine, aranidipine, azelnidipine, barnidipine,benidipine, cilnidipine, clevidipine, isradipine, efonidipine,felodipine, lacidipine, lercanidipine, manidipine, nicardipine,nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine,pranidipine, verapamil or diltiazem or a pharmaceutically acceptablesalt of one of these. A preferred CCB is amlodipine or apharmaceutically acceptable salt thereof.

Accordingly, the COMPOUND or a pharmaceutically acceptable salt thereof[especially a crystalline form of COMPOUND according to any one ofembodiments 1) to 21)] according to any one of embodiments 41) to 51)can be for use in combination with an ACE inhibitor, an ARB, and/or aCCB. The corresponding combined treatment may be effectedsimultaneously, separately, or over a period of time (especiallysimultaneously).

“Simultaneously”, when referring to an administration type, means in thepresent application that the administration type concerned consists inthe administration of two or more active ingredients and/or treatmentsat approximately the same time; wherein it is understood that asimultaneous administration will lead to exposure of the subject to thetwo or more active ingredients and/or treatments at the same time. Whenadministered simultaneously, said two or more active ingredients may beadministered in a fixed dose combination, or in an equivalent non-fixeddose combination (e.g. by using two or more different pharmaceuticalcompositions to be administered by the same route of administration atapproximately the same time), or by a non-fixed dose combination usingtwo or more different routes of administration; wherein saidadministration leads to essentially simultaneous exposure of the subjectto the two or more active ingredients and/or treatments. For example,when used in combination with an ACE inhibitor, an ARB, and/or a CCB,the COMPOUND would possibly be used “simultaneously”. Likewise, whenused in combination with a diuretic, the COMPOUND would possibly be used“simultaneously”.

“Fixed dose combination”, when referring to an administration type,means in the present application that the administration type concernedconsists in the administration of one single pharmaceutical compositioncomprising the two or more active ingredients.

“Separately”, when referring to an administration type, means in thepresent application that the administration type concerned consists inthe administration of two or more active ingredients and/or treatmentsat different points in time; wherein it is understood that a separateadministration will lead to a treatment phase (e.g. at least 1 hour,notably at least 6 hours, especially at least 12 hours) where thesubject is exposed to the two or more active ingredients and/ortreatments at the same time; but a separate administration may also leadto a treatment phase where for a certain period of time (e.g. at least12 hours, especially at least one day) the subject is exposed to onlyone of the two or more active ingredients and/or treatments. Separateadministration especially refers to situations wherein at least one ofthe active ingredients and/or treatments is given with a periodicitysubstantially different from daily (such as once or twice daily)administration (e.g. wherein one active ingredient and/or treatment isgiven e.g. once or twice a day, and another is given e.g. every otherday, or once a week or at even longer distances).

By administration “over a period of time” is meant in the presentapplication the subsequent administration of two or more activeingredients and/or treatments at different times. The term in particularrefers to an administration method according to which the entireadministration of one of the active ingredients and/or treatments iscompleted before the administration of the other/the others begins. Inthis way it is possible to administer one of the active ingredientsand/or treatments for several months before administering the otheractive ingredient(s) and/or treatment(s).

53) Also preferably, the COMPOUND or pharmaceutically acceptable saltthereof [especially a crystalline form of COMPOUND according to any oneof embodiments 1) to 21)] according to any one of embodiments 41) to 51)will be for use in combination with a diuretic (in particular for use incombination with hydrochlorothiazide (HCT)).

Accordingly, the COMPOUND or a pharmaceutically acceptable salt thereof[especially a crystalline form of COMPOUND according to any one ofembodiments 1) to 21)] according to any one of embodiments 41) to 51)can be for use in combination with a diuretic (in particular for use incombination with HCT). The corresponding combined treatment may beeffected simultaneously, separately, or over a period of time(especially simultaneously), as defined hereabove.

54) Yet another embodiment of the invention relates to the use of theCOMPOUND or of a pharmaceutically acceptable salt thereof [especially ofa crystalline form of COMPOUND according to any one of embodiments 1) to21)], for the manufacture of a medicament for use in the treatment of adisorder selected from the group consisting of chronic kidney disease(CKD), diabetes, diabetic nephropathy, diabetic retinopathy, diabeticvasculopathy, chronic heart failure and diastolic dysfunction.

55) One sub-embodiment of embodiment 54) relates to the use according toembodiment 54) which is for the manufacture of a medicament for use inthe treatment of CKD, especially CKD of stages 1 to 4 as defined by theKidney Disease Improving Global Outcomes (KDIGO) Guidelines (and notablyCKD of stage 3), and in particular CKD (notably of these stages) causedby essential hypertension.

56) Another sub-embodiment of embodiment 54) relates to the useaccording to embodiment 54) which is for the manufacture of a medicamentfor use in the treatment of diabetes (that is, type 1 or type 2diabetes).

57) Another sub-embodiment of embodiment 54) relates to the useaccording to embodiment 54) which is for the manufacture of a medicamentfor use in the treatment of diabetic nephropathy.

58) Another sub-embodiment of embodiment 54) relates to the useaccording to embodiment 54) which is for the manufacture of a medicamentfor use in the treatment of diabetic retinopathy.

59) Another sub-embodiment of embodiment 54) relates to the useaccording to embodiment 54) which is for the manufacture of a medicamentfor use in the treatment of diabetic vasculopathy.

60) Another sub-embodiment of embodiment 54) relates to the useaccording to embodiment 54) which is for the manufacture of a medicamentfor use in the treatment of chronic heart failure.

61) According to one variant of sub-embodiment 60), the chronic heartfailure of sub-embodiment 60) will be heart failure with preservedejection fraction.

62) According to another variant of sub-embodiment 60), the chronicheart failure of sub-embodiment 60) will be diastolic heart failure.

63) Another sub-embodiment of embodiment 54) relates to the useaccording to embodiment 54) which is for the manufacture of a medicamentfor use in the treatment of diastolic dysfunction.

64) Preferably, the use according to any one of embodiments 54) to 63)will be such that it is for the manufacture of a pharmaceutical unitdosage form suitable for the oral administration of 2.5 to 100 mg (inparticular 5 or 10 to 50 mg, notably 25 or 50 mg) per day of theCOMPOUND or of a pharmaceutically acceptable salt thereof [especially ofa crystalline form of COMPOUND according to any one of embodiments 1) to21)].

65) Preferably, the use according to any one of embodiments 54) to 64)will be for the manufacture of a medicament for use in combination withan Angiotensin Converting Enzyme (ACE) inhibitor, an AngiotensinReceptor Blocker (ARB) or a Calcium Channel Blocker (CCB) or with apharmaceutically acceptable salt of one of these.

Accordingly, the use according to any one of embodiments 54) to 64) canbe for the manufacture of a medicament for use in combination with anACE inhibitor, an ARB or a CCB or with a pharmaceutically acceptablesalt of one of these. The corresponding combined treatment may beeffected simultaneously, separately, or over a period of time(especially simultaneously).

66) Also preferably, the use according to any one of embodiments 54) to64) will be for the manufacture of a medicament for use in combinationwith a diuretic (in particular for the manufacture of a medicament foruse in combination with hydrochlorothiazide (HCT)).

Accordingly, the use according to any one of embodiments 54) to 64) canbe for the manufacture of a medicament for use in combination with adiuretic (in particular for the manufacture of a medicament for use incombination with HCT). The corresponding combined treatment may beeffected simultaneously, separately, or over a period of time(especially simultaneously), as defined hereabove.

67) Yet another embodiment of the invention relates to a method fortreating a disorder selected from the group consisting of chronic kidneydisease (CKD), diabetes, diabetic nephropathy, diabetic retinopathy,diabetic vasculopathy, chronic heart failure and diastolic dysfunctionin a patient, said method comprising the administration of atherapeutically effective amount of the COMPOUND or of apharmaceutically acceptable salt thereof [especially of a crystallineform of COMPOUND according to any one of embodiments 1) to 21)], to apatient in need thereof.

68) One sub-embodiment of embodiment 67) relates to the method accordingto embodiment 67) which is for treating CKD in a patient, especially CKDof stages 1 to 4 as defined by the Kidney Disease Improving GlobalOutcomes (KDIGO) Guidelines (and notably CKD of stage 3), and inparticular CKD (notably of these stages) caused by essentialhypertension.

69) Another sub-embodiment of embodiment 67) relates to the methodaccording to embodiment 67) which is for treating diabetes (that is,type 1 or type 2 diabetes).

70) Another sub-embodiment of embodiment 67) relates to the methodaccording to embodiment 67) which is for treating diabetic nephropathy.

71) Another sub-embodiment of embodiment 67) relates to the methodaccording to embodiment 67) which is for treating diabetic retinopathy.

72) Another sub-embodiment of embodiment 67) relates to the methodaccording to embodiment 67) which is for treating diabetic vasculopathy.

73) Another sub-embodiment of embodiment 67) relates to the methodaccording to embodiment 67) which is for treating chronic heart failure.

74) According to one variant of sub-embodiment 73), the chronic heartfailure of sub-embodiment 73) will be heart failure with preservedejection fraction.

75) According to another variant of sub-embodiment 73), the chronicheart failure of sub-embodiment 73) will be diastolic heart failure.

76) Another sub-embodiment of embodiment 67) relates to the methodaccording to embodiment 67) which is for treating diastolic dysfunction.

77) Preferably, the method according to any one of embodiments 67) to76) will be such that a dose of 2.5 to 100 mg (in particular 5 or 10 to50 mg, notably 25 or 50 mg) per day of the COMPOUND or of apharmaceutically acceptable salt thereof [especially of a crystallineform of COMPOUND according to any one of embodiments 1) to 21)] isadministered orally to a patient in need thereof.

78) Preferably, the method according to any one of embodiments 67) to77) will such that a therapeutically effective amount of the COMPOUND orof a pharmaceutically acceptable salt thereof [especially of acrystalline form of COMPOUND according to any one of embodiments 1) to21)] is administered in combination with a therapeutically effectiveamount of an Angiotensin Converting Enzyme (ACE) inhibitor, anAngiotensin Receptor Blocker (ARB) or a Calcium Channel Blocker (CCB) orof a pharmaceutically acceptable salt of one of these.

Accordingly, the method according to any one of embodiments 67) to 77)can be such that a therapeutically effective amount of the COMPOUND orof a pharmaceutically acceptable salt thereof [especially of acrystalline form of COMPOUND according to any one of embodiments 1) to21)] is administered in combination with a therapeutically effectiveamount of an ACE inhibitor, an ARB or a CCB or of a pharmaceuticallyacceptable salt of one of these. The corresponding combined treatmentmay be effected simultaneously, separately, or over a period of time(especially simultaneously).

79) Also preferably, the method according to any one of embodiments 67)to 77) will such that a therapeutically effective amount of the COMPOUNDor of a pharmaceutically acceptable salt thereof [especially of acrystalline form of COMPOUND according to any one of embodiments 1) to21)] is administered in combination with a therapeutically effectiveamount of a diuretic (in particular in combination with atherapeutically effective amount of hydrochlorothiazide (HCT)).

Accordingly, the method according to any one of embodiments 67) to 77)can be such that a therapeutically effective amount of the COMPOUND orof a pharmaceutically acceptable salt thereof [especially of acrystalline form of COMPOUND according to any one of embodiments 1) to21)] is administered in combination with a therapeutically effectiveamount of a diuretic (in particular in combination with atherapeutically effective amount of HCT). The corresponding combinedtreatment may be effected simultaneously, separately, or over a periodof time (especially simultaneously).

Particular embodiments of the invention are described in the followingExamples, which serve to illustrate the invention in more detail withoutlimiting its scope in any way.

EXPERIMENTAL PROCEDURES

Abbreviations:

The following abbreviations are used throughout the specification andthe examples:

Ac acetyl

AcOH acetic acid

aq. aqueous

DCM dichloromethane

DMSO dimethylsulfoxide

EtOAc ethyl acetate

eq. equivalent(s)

FTIR Fourier Transform Infrared Spectroscopy or Spectrum

HPLC High Performance Liquid Chromatography

iPrOAc isopropyl acetate

MeOH methanol

MIBK methyl iso-butyl ketone

org. organic

rt room temperature

THF tetrahydrofuran

vol. volume(s)

w/w weight-per-weight ratio

wt. weight unit

XRPD X-ray powder diffraction

EXAMPLES

Method for Obtaining XRPD Patterns

All XRPD patterns for the solid forms described herein have beenobtained as described hereafter. X-ray powder diffraction patterns werecollected on a Bruker D8 Advance X-ray diffractometer equipped with aLynxeye detector operated with CuKα-radiation in reflection mode(coupled two Theta/Theta). Typically, the X-ray tube was run at of 40kV/40 mA. A step size of 0.02° 2θ) and a step time of 76.8 sec over ascanning range of 3-50° in 20 were applied. The divergence slit was setto fixed 0.3. Powders were slightly pressed into a silicon singlecrystal sample holder with depth of 0.5 mm and samples were rotated intheir own plane during the measurement. Diffraction data are reportedusing combined Cu Kα1 and Kα2 radiation, without Kα2 stripping. Theaccuracy of the 20 values as provided herein is in the range of+/−0.1-0.2° as it is generally the case for conventionally recordedX-ray powder diffraction patterns.

Gravimetric Vapour Sorption (GVS)

Measurements are performed on a multi sample instrument SPS-100n(Projekt Messtechnik, Ulm, Germany) operated in stepping mode at 25° C.The sample is allowed to equilibrate at 40% RH before starting apre-defined humidity program (40-0-95-0-95-40% RH, steps of 5% ΔRH andwith a maximal equilibration time of 24 hours per step are applied.About 20 to 30 mg of each sample is used.

The hygroscopic classification is done according to the EuropeanPharmacopeia Technical Guide (1999, page 86), e.g., slightlyhygroscopic: increase in mass is less than 2% and equal to or greaterthan 0.2% mass/mass; hygroscopic: increase in mass is less than 15% andequal to or greater than 2% mass/mass. The mass change between 40%relative humidity and 80% relative humidity in the first adsorption scanis considered.

Differential Scanning Calorimetry (DSC)

DSC data are collected on a Mettler Toledo STARe System (DSC822e module,measuring cell with ceramic sensor and STAR software version 9.20)equipped with a 34-position auto-sampler. The instrument is calibratedfor energy and temperature using certified indium. Typically, 1-5 mg ofeach sample, in an automatically pierced aluminium pan, is heated at 10°C. min−1, unless stated otherwise, from −20° C. to 280° C. A nitrogenpurge at 20 mL min−1 is maintained over the sample. Peak temperaturesare reported for melting points.

Thermogravimetric Analysis (TGA)

TGA data are collected on a Mettler Toledo STARe System (TGA851e moduleand STAR software version 9.20) equipped with a 34 positionauto-sampler. Typically about 5 mg of a sample, in an automaticallypierced aluminium pan, is heated at 10° C. min⁻¹, unless statedotherwise, from 30° C. to 250° C. A nitrogen purge at 10 mL min−1 ismaintained over the sample.

Example 1 Form A

1.1. A 3 L double jacketed reactor was charged with5-(4-bromophenyl)-4-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)-6-fluoropyrimidine(100 g, 0.213 mol, 1 eq. (WO2015/121397)), sulfamide (40.9 g, 0.425 mol,2.0 eq.), K₂CO₃ (147 g, 1.06 mol, 5 eq.) and DMSO (500 mL, 5 vol.) dopedwith water (2 mL, 0.111 mol, 0.5 eq.). The heterogeneous mixture washeated to 70° C. during ca. 3 h, after which time complete conversionwas observed. After cooling to 20° C., most of the inorganic saltfreight was removed by filtration. The filter cake was washed withEtOAc/iPrOAc 1:1 (300 mL, 3 vol.). Celite (100 g, 1 wt.) topped with alayer of charcoal (20 g, 0.2 wt.) was preconditioned with EtOAc/iPrOAc1:1 (500 mL, 5 vol.) (filtrate discarded). The reaction mixture wasfiltered over this cake and rinsed with EtOAc/iPrOAc 1:1 (300 mL, 3vol.). Then 1M aq. NaOAc solution (500 mL, 0.5 mol, 2.3 eq, 5 vol.) wasadded while keeping the temperature at 25-35° C. The aq. phase waswashed a second time with EtOAc/iPrOAc 1:1 (500 mL, 5 vol.). To the aq.phase, 1M H₂SO₄ (200 mL, 0.2 mol, 1 eq., 2 vol.) was added during 1 h at25-30° C. Crystallization started at pH 8.5-8.0. The crude product wasfiltered off as XRPD pattern form K (DMSO solvate) or a mixture of formA and form K. It was washed twice with water (2×1000 mL, 2×10 vol.). Thesolid was slurried in water (1000 mL, 10 vol.) at rt for 3 h. The solidwas filtered off and slurried a second time in water (1000 mL, 10 vol.)at rt for 3 h. After washing with water (1000 mL, 10 vol.), the pureproduct was dried in vacuum at 40° C. to afford{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamideas a white to off-white solid (75 g, 65% yield, XRPD pattern form A).

1.2. A reactor (200 L Hastelloy) was charged with5-(4-bromophenyl)-4-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)-6fluoropyrimidine (24.2 kg, 51.5 mol), sulfamide (9.7 kg, 100.9 mol, 1.96eq.), potassium carbonate (35.5 kg, 256.9 mol, 5.0 eq.), DMSO (133 kg, 5vol.) and water (490 g, 27.2 mol, 0.53 eq.). The contents of the reactorwere heated to 70-75° C. Monitoring by HPLC showed complete conversionin 4 hours. The contents were cooled to 20-25° C. and the solids werecentrifuged off. Each load was washed with EtOAc/iPrOAc 1:1 (65 kg,3vol.). The filtrate was re-charged in the reactor and charcoal (2.4kg,10%w/w) and Celite® (4.8 kg, 20% w/w) were added. The contents wereagitated for 1 h at 15-20° C. and filtered through a cartridge filterback into the reactor. The filters were rinsed with EtOAc/iPrOAc 1:1 (43kg, 2 vol.). NaOAc (8% in water) (124 kg, 5 vol.) was added over 2 h,keeping the temperature below 25° C. After phase separation, the aq.layer was washed with EtOAc/iPrOAc 1: 1 (109 kg, 5 vol.) at 20-25° C.Sulfuric acid (5% in water; 64 L, 32.6 mol, 0.63 eq.) was added to theaq. layer at 25-30° C. over 2 hours to reach pH 6.4. The contents werethen cooled to 15-20° C. for 1 h. The solids were filtered off andwashed twice with water (2×24 L, 2×1 vol.). The solid was slurried twicein water (2×242 kg, 2×10 vol.) at 15-20° C. for 3 hours each, filteredand dried, to yield5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamideas a white solid (21.6 kg, 77% yield, XRPD pattern Form A).

Example 2 Form B (DCM Solvate of the COMPOUND)

5-(4-bromophenyl)-4-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)-6fluoropyrimidine (10.0 g, 21.3 mmol, 1.00 eq.), sulfamide (4.1 g, 42.5mmol, 2.0 eq.) and K₂CO₃ (14.7 g, 106 mmol, 5.0 eq.) were suspended inDMSO (50 mL, 5 vol.) and heated to 70° C. for 5 h. The mixture wascooled to rt and EtOAc (40 mL, 4 vol.) followed by water (100 mL, 10vol.) were added. After separation of the layers (org. phase discarded),the aq. phase was extracted with DCM (100 mL, 10 vol.). The DCM layerwas acidified from pH 11.5 to pH 7.0 with conc. AcOH (3 mL, 52 mmol, 2.5eq.), resulting in crystallization of the product. The suspension wascooled to 0° C. for 1 h, then to −5° C. for 15 min. The solid wasfiltered, washed with cold DCM (10 mL, 1 vol.) and dried to yield a DCMsolvate of{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamidein Form B as a white solid (9.8 g, 84% yield).

Example 3 Form C

0.2 mL of a stock solution of{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamidedissolved in THF at 50 mg/mL was dispensed to 3 vials. The solvent wasevaporated for 90 min in a Combidancer device from Hettich AG (Bach,Switzerland) operated at 35° C. and 200 mbar. Immediately thereafter0.015 mL of MeOH for the first vial, EtOH for the second vial and iPrOHfor the third vial was added and the vials were allowed to stand closedfor 3 days. Solid residue of{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamidein Form C was obtained for each of these solvents.

Example 4 Form D

4.1. A reactor was charged with sulfamide (2.00 eq.), K₂CO₃ (5.00 eq.),5-(4-bromophenyl)-4-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)-6-fluoropyrimidine(1.00 eq.), DMSO (5.0 vol.) and water (0.02 vol.). The mixture washeated to 75° C. for 2 h. After cooling to 23° C., the suspension wasfiltered and rinsed with EtOAc/iPrOAc 1:1 (5.5 vol.) through thereactor. The filtrate was again filtered through an in-line filter andrinsed with EtOAc/iPrOAc 1:1 (1.5 vol.). A solution of 1M NaOAc in water(5.0 vol.) was added at 27° C., and the layers were separated. The aq.phase was washed with EtOAc/iPrOAc 1:1 (5.0 vol.). The aq. phase wasacidified to pH 5.8 using 0.5M H₂SO₄ in water (2.35 vol.) over 2.5 h,leading to crystallization. After 1 h stirring at 20° C., the suspensionwas filtered and washed with water (2×10 vol.). The solid was slurriedtwice in water (2×10 vol.) at 20° C. for 3 h each, filtered, washed withwater (10 vol.) and dried to give{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamidein Form D.

4.2. 50 mg of{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamidein Form A was dissolved in 3 mL methyl-ethylketone in a new 7 mL glassvial. After sonication in an ultrasound bath for 1 min, the vial wasallowed to stand open at rt for 3 days. The solid residue was{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamidein Form D.

Example 5 Form E (MeCN Solvate of the COMPOUND)

{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamidein Form A was heated to reflux in 10 volumes of MeCN. After 10 min itwas allowed to cool down to 20° C. within 1 h (heating bath removed). Itwas filtered off and dried under reduced pressure and 45° C. Solidresidue was a MeCN solvate of{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamidein Form E.

Example 6 Form J

The DCM solvate of{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamideForm B (9.4 g, 17.2 mmol, 1.00 eq.) was dissolved in DMSO (19 mL, 2vol.). The solution was added into H₂O (94 mL, 10 vol.) and stirred atrt for 5 min. The resulting suspension was filtered, washed twice withH₂O (2×94 mL, 2×10 vol.) and dried to provide{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamideForm J as a white solid (6.8 g, 72% yield).

Example 7 Form K (DMSO Solvate of the COMPOUND)

7.1.{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamideForm A (1.00 g, 1.83 mmol, 1.00 eq.) was dissolved in DMSO (2 mL, 2vol.). To this solution, 10% H₂O in DMSO (10 mL, 10 vol.) was addedslowly, followed by pure H₂O (2 mL, 2 vol.). Seeding with form Ktriggered crystallization of the product. The suspension was filtered,washed with H₂O (5×10 mL, 5×10 vol.) and dried to give a DMSO solvate{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamidein Form K as a white solid (0.95 g, 95% yield).

7.2.5-(4-bromophenyl)-4-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)-6-fluoropyrimidine(10.0 g, 21.3 mmol, 1.00 eq.), sulfamide (4.1 g, 42.5 mmol, 2.0 eq.) andK₂CO₃ (14.7 g, 106 mmol, 5.0 eq.) were suspended in DMSO (50 mL, 5 vol.)and heated to 50° C. for 20 h. The mixture was cooled to rt and MIBK(100 mL, 10 vol.) followed by water (100 mL, 10 vol.) were added. Afterseparation of the layers (org. phase discarded), the aq. phase wasacidified from pH 11.4 to pH 6.5 with conc. AcOH (4 mL, 70 mmol, 3.3eq.), resulting in crystallization of the product. The solid wasfiltered, washed with water (4×50 mL, 4×5 vol.) and dried to afford aDMSO solvate of{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamidein Form K as a beige solid (10.4 g, 90% yield).

Example 8 Form L (EtOH Solvate of the COMPOUND)

The DMSO solvate of{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamideForm K (100 mg, 0.183 mmol, 1.00 eq.) was slurried in EtOH (0.5 mL, 5vol.) at rt for 4 h. The suspension was filtered, washed twice with H₂O(2×0.5 mL, 2×5 vol.) and dried to afford an EtOH solvate of{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamidein Form L as a white solid (40 mg, 40% yield).

Example 9 ACT-132577 Tablets

Tablets containing each 50 mg of COMPOUND can be prepared using a wetgranulation process. The tablet composition is the following:

ACT-132577 tablets (250 mg) Material (Chemical name) mg/tablet Weight%/tablet Intra- COMPOUND (amorphous, or 50.00 20.00 granular solid formA or solid form C, as described herein) Microcrystalline cellulose 61.5024.60 Lactose (200M) 122.25 48.90 Hydroxypropylcellulose 5.50 2.20Croscarmellose sodium 4.50 1.80 Water qs qs Extra- Croscarmellose sodium5.00 2.00 granular Magnesium stearate 1.25 0.50 Total 250.00 100.00 qs =quantity sufficient

Preferably, COMPOUND in crystalline Form A (as described herein) will beused for making the tablets.

Example 10 ACT-132577 Tablets

The tablets of Example 9 can be coated with a layer of Aquapolish® whiteMS or Aquapolish® white PVA (coating manufacturer: Biogrund).

Example 11 ACT-132577 Tablets

Tablets containing each 50 mg of COMPOUND can be prepared using a wetgranulation process. The tablet composition is the following:

ACT-132577 tablets (250 mg) Material (Chemical name) mg/tablet Weight%/tablet Intra- COMPOUND (amorphous, or 50.00 20.00 granular solid formA or solid form C, as described herein) Microcrystalline cellulose 61.2524.50 Lactose (200M) 122.50 49.00 Hydroxypropylcellulose 5.00 2.00Croscarmellose sodium 5.00 2.00 Water qs qs Extra- Croscarmellose sodium5.00 2.00 granular Magnesium stearate 1.25 0.50 Total 250.00 100.00 qs =quantity sufficient

Preferably, COMPOUND in crystalline Form A (as described herein) will beused for making the tablets.

Example 12

The tablets of Example 11 can be coated with a layer of Aquapolish®white MS or Aquapolish® white PVA (coating manufacturer: Biogrund).

Example 13 ACT-132577 Tablets

Tablets containing each 12.5 mg of COMPOUND can be prepared using a wetgranulation process. The tablet composition is the following:

ACT-132577 tablets (100 mg) Material (Chemical name) mg/tablet Weight%/tablet Intra- COMPOUND (amorphous, or 12.50 12.50 granular solid formA or solid form C, as described herein) Microcrystalline cellulose 27.0027.00 Lactose (200M) 54.00 54.00 Hydroxypropylcellulose 2.00 2.00Croscarmellose sodium 2.00 2.00 Water qs qs Extra- Croscarmellose sodium2.00 2.00 granular Magnesium stearate 0.50 0.50 Total 100.00 100.00 qs =quantity sufficient

Preferably, COMPOUND in crystalline Form A (as described herein) will beused for making the tablets.

Example 14 ACT-132577 Tablets

The tablets of Example 13 can be coated with a layer of Aquapolish®white MS or Aquapolish® white PVA (coating manufacturer: Biogrund).

Example 15 ACT-132577 Tablets

Tablets containing each 12.5 mg of COMPOUND can be prepared using a wetgranulation process. The tablet composition is the following:

ACT-132577 tablets (100 mg) Material (Chemical name) mg/tablet Weight%/tablet Intra- COMPOUND (amorphous, or 12.50 12.50 granular solid formA or solid form C, as described herein) Microcrystalline cellulose 27.5027.50 Lactose (200M) 53.50 53.50 Hydroxypropylcellulose 2.20 2.20Croscarmellose sodium 1.80 1.80 Water qs qs Extra- Croscarmellose sodium2.00 2.00 granular Magnesium stearate 0.50 0.50 Total 100.00 100.00 qs =quantity sufficient

Preferably, COMPOUND in crystalline Form A (as described herein) will beused for making the tablets.

Example 16 ACT-132577 Tablets

The tablets of Example 15 can be coated with a layer of Aquapolish®white MS or Aquapolish® white PVA (coating manufacturer: Biogrund).

Properties of the Crystalline Forms

Storage at Room Temperature

A sample of Form A crystals of the COMPOUND (as obtained according toExample 1 above) has been stored at a temperature of 20-25° C. at 92%relative humidity for 2 months. X-ray powder diffraction performed onthat sample at the end of the 2 months showed that the sample was stillconsisting only in Form A crystals of the COMPOUND. The same result wasobtained after storage for 8 weeks under the above conditions. HPLCcontrol of the sample after 8 weeks storage revealed no significantchange in peak area %, i.e. no significant degradation was observedunder such conditions.

A sample of Form B crystals of a dichloromethane solvate of the COMPOUND(as obtained according to Example 2 above) has been stored in a closedvial (20 mg of Form B crystals being placed in a closed 4 mL vial) at atemperature of 20-25° C. for about 3 weeks. X-ray powder diffractionperformed on that sample at the end of the 3 weeks showed that the FormB crystals were transformed into Form A crystals of the COMPOUND.

A sample of Form K crystals of a dimethylsulfoxide solvate of theCOMPOUND (as obtained according to Example 7 above) has been stored in aclosed vial (20 mg of Form K crystals being placed in a closed 4 mLvial) at a temperature of 20-25° C. for about 3 weeks. X-ray powderdiffraction performed on that sample at the end of the 3 weeks showedthat the Form K crystals were transformed into Form A crystals of theCOMPOUND.

DSC

Form A of COMPOUND (as obtained by example 1) melts and decomposesconcomitantly. By DSC an endothermic/exothermic signal is observed, witha peak of the endotherm observed at about 159° C.

Form C of COMPOUND (as obtained by example 3) melts and decomposesconcomitantly. By DSC an endothermic/exothermic signal is observed, witha peak of the endotherm observed at about 153° C.

Hygroscopicity

Form A e.g. as obtained from Example 1 is considered to benon-hygroscopic as determined by gravimetric vapor sorption (GVS) (seeFIG. 19).

Form C e.g. as obtained from Example 3 is considered to be slightlyhygroscopic as determined by gravimetric vapor sorption (GVS) (see FIG.20).

EXAMPLES OF THERAPEUTIC USES OF APROCITENTAN Example A Acute Effects ofCOMPOUND in Dahl Salt-Sensitive Rats:

The acute effects of COMPOUND on blood pressure, in particular on meanarterial blood pressure (hereafter “MAP”), and heart rate (hereafter“HR”) were evaluated by means of telemetry in conscious, malehypertensive Dahl salt-sensitive rats (hereafter “Dahl-S rats”—seedetails about this model in Rapp, Hypertension (1982), 4, 753-763).

Elevated blood pressure is induced in Dahl-S rats by providing 1% sodiumchloride in drinking water. Groups of 6-7 Dahl-S rats were used for thevehicle (7.5% gelatin aquous solution) and each dose of COMPOUND tested(0.3, 1, 3, 10, 30, 100, and 300 mg/kg). Effects of COMPOUND on HR andMAP were calculated for individual animals relative to the 24 h periodbefore administering. The results obtained regarding MAP (maximal MAPdecrease observed over 6 consecutive hours) are summarised in FIG. 9(data are presented as mean±standard error of the mean). In summary, adose of 10 mg/kg COMPOUND decreased MAP by 19±4 mm Hg in Dahl-S rats. Incontrast to MAP, HR was not affected.

Example B Acute Effects of COMPOUND in Deoxycorticosterone Acetate SaltRats

The acute effects of COMPOUND on blood pressure, in particular on meanarterial blood pressure (hereafter “MAP”), and heart rate (hereafter“HR”) were evaluated by means of telemetry in conscious, malehypertensive deoxycorticosterone acetate salt rats (hereafter “DOCA-saltrats”—see details about this model in Gavras et al., Circ. Res. (1975),36, 300-309).

In the DOCA-salt rats, hypertension is induced by the combination ofunilateral nephrectomy, implantation of pellets of the mineralocorticoidanalog DOCA, and provision of 1% sodium chloride in drinking water.Groups of 6-11 DOCA-salt rats were used for the vehicle (7.5% gelatinaquous solution) and each dose of COMPOUND tested (0.3, 1, 3, 10, 30,100, and 300 mg/kg). Effects of COMPOUND on HR and MAP were calculatedfor individual animals relative to the 24 h period before administering.The results obtained regarding MAP (maximal MAP decrease observed over 6consecutive hours) are summarised in FIG. 10 (data are presented asmean±standard error of the mean). In summary, a dose of 10 mg/kgCOMPOUND decreased MAP by 29±6 mm Hg in DOCA-salt rats. In contrast toMAP, HR was not affected.

Example C Acute Effects of COMPOUND in Spontaneously Hypertensive Rats

The acute effects of COMPOUND on blood pressure, in particular on meanarterial blood pressure (hereafter “MAP”), and heart rate (hereafter“HR”) were evaluated by means of telemetry in conscious, malespontaneously hypertensive rats (hereafter “SHRs”—see details about thismodel in Atanur et al., Genome Res. (2010), 20, 791-803).

Groups of 4-6 SHRs were used for the vehicle (7.5% gelatin aquoussolution) and each dose of COMPOUND tested (1, 3, 10, 30, 100, and 300mg/kg). Effects of COMPOUND on HR and MAP were calculated for individualanimals relative to the 24 h period before administering. The resultsobtained regarding MAP (maximal MAP decrease observed over 6 consecutivehours) are summarised in FIG. 11 (data are presented as mean±standarderror of the mean). In summary, a dose of 100 mg/kg COMPOUND decreasedMAP by 18±4 mm Hg in SHRs. In contrast to MAP, HR was not affected.

Example D Acute Effects of COMPOUND, Alone or in Combination withValsartan, in Spontaneously Hypertensive Rats

The acute effects of COMPOUND administered orally at a single dose of100 mg/kg on blood pressure, in particular on mean arterial bloodpressure (hereafter “MAP”), and heart rate (hereafter “HR”), withCOMPOUND being used either alone or in combination with valsartanadministered orally at a single dose of 10 mg/kg, were evaluated bymeans of telemetry in conscious, male spontaneously hypertensive rats(hereafter “SHRs”—see details about this model in Atanur et al., GenomeRes. (2010), 20, 791-803).

6 SHRs per treatment group were used for this test. The results obtainedregarding MAP are summarised in FIG. 12 wherein each data point ispresented as a 6-hour mean (NB: the expected additive effect of thecombination of the two drugs, referred to as “Predicted additiveeffect”, was calculated by adding the decreases in blood pressure valuesobtained after administration of each compound separately); the vehicle(7.5% gelatin aquous solution) treatment had no effect on MAP or HR andthe results obtained are therefore not represented in the figure. Inbrief, co-administration of COMPOUND and valsartan decreased MAP beyondthe predicted (calculated) values, demonstrating synergism between thetwo molecules. In contrast to MAP, HR was not affected in any of thetreatment groups.

Example E Acute Effects of COMPOUND, Alone or in Combination withValsartan, in Deoxycorticosterone Acetate Salt Rats

The acute effects of COMPOUND administered orally at a single dose of 10mg/kg on blood pressure, in particular on mean arterial blood pressure(hereafter “MAP”), and heart rate (hereafter “HR”), with COMPOUND beingused either alone or in combination with valsartan administered orallyat a single dose of 30 mg/kg, were evaluated by means of telemetry inconscious, male hypertensive deoxycorticosterone acetate salt rats(hereafter “DOCA-salt rats”—see details about this model in Gavras etal., Circ. Res. (1975), 36, 300-309).

In the DOCA-salt rats, hypertension is induced by the combination ofunilateral nephrectomy, implantation of pellets of the mineralocorticoidanalog DOCA, and provision of 1% sodium chloride in drinking water. 7-8DOCA-salt rats per treatment group were used for this test. The resultsobtained regarding MAP are summarised in FIG. 13 wherein each data pointis presented as a 6-hour mean (NB: the expected additive effect of thecombination of the two drugs, referred to as “Predicted additiveeffect”, was calculated by adding the decreases in blood pressure valuesobtained after administration of each compound separately); the vehicle(4% gelatin aquous solution) treatment had no effect on MAP or HR andthe results obtained are therefore not represented in the figure. Inbrief, co-administration of COMPOUND and valsartan decreased MAP beyondthe predicted (calculated) values, demonstrating synergism between thetwo molecules. In contrast to MAP, HR was not affected in any of thetreatment groups.

Example F Acute Effects of COMPOUND, Alone or in Combination withEnalapril, in Spontaneously Hypertensive Rats

The acute effects of COMPOUND administered orally at a single dose of100 mg/kg on blood pressure, in particular on mean arterial bloodpressure (hereafter “MAP”), and heart rate (hereafter “HR”), withCOMPOUND being used either alone or in combination with enalapriladministered orally at a single dose of 3 mg/kg, were evaluated by meansof telemetry in conscious, male spontaneously hypertensive rats(hereafter “SHRs”—see details about this model in Atanur et al., GenomeRes. (2010), 20, 791-803).

7 SHRs per treatment group were used for this test. The results obtainedregarding MAP are summarised in FIG. 14 wherein each data point ispresented as a 6-hour mean (NB: the expected additive effect of thecombination of the two drugs, referred to as “Predicted additiveeffect”, was calculated by adding the decreases in blood pressure valuesobtained after administration of each compound separately); the vehicle(4% gelatin aqueous solution) treatment had no effect on MAP or HR andthe results obtained are therefore not represented in the figure. Inbrief, co-administration of COMPOUND and enalapril decreased MAP beyondthe predicted (calculated) values, demonstrating synergism between thetwo molecules. In contrast to MAP, HR was not affected in any of thetreatment groups.

Example G Acute Effects of COMPOUND, Alone or in Combination withAmlodipine, in Deoxycorticosterone Acetate Salt Rats

The acute effects of COMPOUND administered orally at a single dose of 10mg/kg on blood pressure, in particular on mean arterial blood pressure(hereafter “MAP”), and heart rate (hereafter “HR”), with COMPOUND beingused either alone or in combination with amlodipine administered orallyat a single dose of 1 mg/kg, were evaluated by means of telemetry inconscious, male hypertensive deoxycorticosterone acetate salt rats(hereafter “DOCA-salt rats”—see details about this model in Gavras etal., Circ. Res. (1975), 36, 300-309).

In the DOCA-salt rats, hypertension is induced by the combination ofunilateral nephrectomy, implantation of pellets of the mineralocorticoidanalog DOCA, and provision of 1% sodium chloride in drinking water. 6-8DOCA-salt rats per treatment group were used for this test. The resultsobtained regarding MAP are summarised in FIG. 15 wherein each data pointis presented as a 6-hour mean (NB: the expected additive effect of thecombination of the two drugs, referred to as “Predicted additiveeffect”, was calculated by adding the decreases in blood pressure valuesobtained after administration of each compound separately); the vehicle(4% gelatin aquous solution) treatment had no effect on MAP or HR andthe results obtained are therefore not represented in the figure. Inbrief, co-administration of COMPOUND and amlodipine decreased MAP beyondthe predicted (calculated) values, demonstrating synergism between thetwo molecules. In contrast to MAP, HR was not affected in any of thetreatment groups.

Example H Chronic Effects of COMPOUND in Deoxycorticosterone AcetateSalt Rats

The chronic effects of repeated administrations of doses of 1, 10 and100 mg/kg/day of COMPOUND, in particular mean arterial blood pressure(hereafter “MAP”), and heart rate (hereafter “HR”), were evaluated inconscious, male hypertensive deoxycorticosterone acetate salt rats(hereafter “DOCA-salt rats”—see details about this model in Gavras etal., Circ. Res. (1975), 36, 300-309). In the DOCA-salt rats,hypertension is induced by the combination of unilateral nephrectomy,implantation of pellets of the mineralocorticoid analog DOCA, andprovision of 1% sodium chloride in drinking water. The results of theDOCA-salt rats treated with COMPOUND were compared to those obtained forWistar rats or for DOCA-salt rats that received only the vehicle (4%gelatin aquous solution).

a) The results obtained regarding MAP are summarised in FIG. 16 whereineach data point is presented as a 24-hour mean. 6 rats were used foreach of the 5 test groups (Wistar control rats [bottom line], DOCA-saltcontrol rats [2^(nd) line from top at day 28] and DOCA-salt ratsreceiving repeated administrations of doses of 1 mg/kg/day [top line atday 28], 10 mg/kg/day [3^(rd) line from top at day 28] and 100 mg/kg/day[4^(th) line from top at day 28] of COMPOUND). In brief, oraladministration of COMPOUND for 4 weeks dose-dependently attenuated theDOCA-salt-induced increase in MAP without changing HR.

b) The results obtained regarding renal vascular resistance aresummarised in FIG. 17 wherein:

-   -   DOCA Ø2w represents DOCA-salt rats sacrificed just before        initiation of treatment with COMPOUND; and    -   the “*” symbol in represents a statistical significance factor        p<0.05 when using a one way ANOVA followed by a Newmal-Keuls        multiple comparisons post-hoc test.

In summary, based on these tests, chronic oral administration ofCOMPOUND to

DOCA-salt rats dose-dependently increased renal blood flow and decreasedrenal vascular resistance. COMPOUND also tended to decrease leftventricular hypertrophy, as suggested by the dose-dependent decrease inplasma concentrations of N-terminal pro-brain natriuretic peptide(NTproBNP).

Example I Effects of COMPOUND, Alone or in Combination with an ACEInhibitor or an ARB, in Animal Models of Diabetes

The effects of COMPOUND can be assessed in diabetic rodent models (inthis regard, see the models described in the following references: Senet al, Life Sci. (2012), 91(13-14), 658-668; Janiak et al., Eur. J.Pharmacol. (2006), 534, 271-279; and Iglarz et al, J. Pharmacol. Exp.Ther. (2008), 327(3), 736-745). In particular, the effect of COMPOUND,alone or in combination, on glucose tolerance, insulinemia and end organdamage can be investigated. End organ damage includes: vascularfunction, renal function (e.g. proteinuria), cardiac function andremodeling and any other target organ affected by diabetes (e.g. theeye).

Example J Evaluation of the Effect of COMPOUND on Fluid Retention

A decrease in haematocrit (Hct) or haemoglobin occurs secondary to anincrease in plasma volume and can be used as a marker of fluidretention. A single oral dose of aprocitentan (1-30 mg/kg) or vehicle(gelatin) was administered by gavage to male Wistar rats. Twenty-fourhours after administration, sublingual blood was sampled underisoflurane-induced anesthesia. Haematocrit was measured using ahematology analyser. COMPOUND did not impact on haematocrit (Hct)suggesting low liability on fluid retention (FIG. 18).

Comparison Example 1 Acute Effects of Spironolactone Used in Combinationwith Valsartan in Spontaneously Hypertensive Rats

The acute effects of spironolactone on blood pressure, in particular onmean arterial blood pressure (hereafter “MAP”), and heart rate(hereafter “HR”) in combination with valsartan, each administered orallyas single doses, were also evaluated by means of telemetry in conscious,male spontaneously hypertensive rats (hereafter “SHRs”—see details aboutthis model in Atanur et al., Genome Res. (2010), 20, 791-803) using aprotocol analog to that described in Example D.

Unlike for COMPOUND, no synergistic effect was seen on MAP reduction forthe combination of spironolactone treatment with valsartan treatment.

Comparison Example 2 Acute Effects of Spironolactone Used in Combinationwith Valsartan in Deoxycorticosterone Acetate Salt Rats

The acute effects of spironolactone on blood pressure, in particular onmean arterial blood pressure (hereafter “MAP”), and heart rate(hereafter “HR”) in combination with valsartan, each administered orallyas single doses, were also evaluated by means of telemetry in conscious,male hypertensive deoxycorticosterone acetate salt rats (hereafter“DOCA-salt rats”—see details about this model in Gavras et al., Circ.Res. (1975), 36, 300-309) using a protocol analog to that described inExample E.

Unlike for COMPOUND, no synergistic effect was seen on MAP reduction forthe combination of spironolactone treatment with valsartan treatment.

Comparison Example 3 Acute Effects of Spironolactone Used in Combinationwith Enalapril in Spontaneously Hypertensive Rats

The acute effects of spironolactone on blood pressure, in particular onmean arterial blood pressure (hereafter “MAP”), and heart rate(hereafter “HR”) in combination with valsartan, each administered orallyas single doses, were also evaluated by means of telemetry in conscious,male spontaneously hypertensive rats (hereafter “SHRs”—see details aboutthis model in Atanur et al., Genome Res. (2010), 20, 791-803) using aprotocol analog to that described in Example F.

Unlike for COMPOUND, no synergistic effect was seen on MAP reduction forthe combination of spironolactone treatment with enalapril treatment.

1. A crystalline form of{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide:

characterized by: the presence of peaks in the X-ray powder diffractiondiagram at the following angles of refraction 2θ: 17.8°, 20.0°, and23.5°; or the presence of peaks in the X-ray powder diffraction diagramat the following angles of refraction 2θ: 9.7°, 15.7°, and 22.0°; or thepresence of peaks in the X-ray powder diffraction diagram at thefollowing angles of refraction 2θ: 4.6°, 16.8°, and 20.1°; or thepresence of peaks in the X-ray powder diffraction diagram at thefollowing angles of refraction 2θ: 9.5°, 16.5°, and 18.2°; wherein saidcrystalline form is an acetonitrile solvate; or the presence of peaks inthe X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 4.0°, 16.1°, and 21.9°; or the presence of peaks in theX-ray powder diffraction diagram at the following angles of refraction2θ: 16.9°, 19.3°, and 24.8°; wherein said crystalline form is adimethylsulfoxide solvate; or the presence of peaks in the X-ray powderdiffraction diagram at the following angles of refraction 2θ: 11.3°,16.4°, and 20.3°; wherein said crystalline form is [[a]]an ethanolsolvate; wherein said X-ray powder diffraction diagram is obtained byusing combined Cu Kα1 and Kα2 radiation, without Kα2 stripping; and theaccuracy of the 2θ values is in the range of 2θ+/−0.2°.
 2. Thecrystalline form of{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamideaccording to claim 1, characterized by: the presence of peaks in theX-ray powder diffraction diagram at the following angles of refraction2θ: 17.8°, 18.6°, 20.0°, 23.2° and 23.5°; or the presence of peaks inthe X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 7.8°, 9.7°, 15.7°, 19.8° and 22.0°; wherein said X-raypowder diffraction diagram is obtained by using combined Cu Kα1 and Kα2radiation, without Kα2 stripping; and the accuracy of the 2θ values isin the range of 2θ+/−0.2°.
 3. The crystalline form of{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamideaccording to claim 1, characterized by the presence of peaks in theX-ray powder diffraction diagram at the following angles of refraction2θ: 17.8°, 18.6°, 20.0°, 23.2° and 23.5°; wherein said X-ray powderdiffraction diagram is obtained by using combined Cu Kα1 and Kα2radiation, without Kα2 stripping; and the accuracy of the 20 values isin the range of 2θ+/−0.2°.
 4. The crystalline form of{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamideaccording to claim 1, characterized by the presence of peaks in theX-ray powder diffraction diagram at the following angles of refraction2θ: 9.8°, 9.9°, 11.7°, 17.8°, 18.6°, 20.0°, 21.5°, 22.8°, 23.2° and23.5°; wherein said X-ray powder diffraction diagram is obtained byusing combined Cu Kα1 and Kα2 radiation, without Kα2 stripping; and theaccuracy of the 2θ values is in the range of 2θ+/−0.2°.
 5. Thecrystalline form of{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamideor of a solvate of that compound, according to claim 3, whichessentially shows the X-ray powder diffraction pattern as depicted inFIG.
 1. 6. The crystalline form of{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide,according to claim 3, wherein said crystalline form is obtainable bycrystallisation of the{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamidein an aqueous solution at pH 6.2 to 6.8.
 7. (canceled)
 8. Apharmaceutical composition comprising as active ingredient a crystallineform of{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamideaccording to claim 2, and at least one therapeutically inert excipient.9. A pharmaceutical composition according to claim 8, which comprises astherapeutically inert excipient microcrystalline cellulose, lactose,hydroxypropylcellulose, croscarmellose sodium and magnesium stearate.10. (canceled)
 11. (canceled)
 12. (canceled)
 13. (canceled)
 14. A methodfor the treatment of hypertension, pulmonary hypertension, coronarydiseases, cardiac insufficiency, renal and myocardial ischemia, renalfailure, cerebral ischemia, dementia, migraine, subarachnoidalhemorrhage, Raynaud's syndrome, digital ulcers or portal hypertension aswell as for the treatment or prevention of atherosclerosis, restenosisafter balloon or stent angioplasty, inflammation, stomach and duodenalulcer, cancer, melanoma, prostate cancer, prostatic hypertrophy,erectile dysfunction, hearing loss, amaurosis, chronic bronchitis,asthma, pulmonary fibrosis, gram negative septicemia, shock, sickle cellanemia, glomerulonephritis, renal colic, glaucoma, connective tissuediseases, diabetic complications, complications of vascular or cardiacsurgery or after organ transplantation, complications of cyclosporintreatment, pain, hyperlipidemia or chronic kidney disease, comprisingadministering to a patient an effective amount of a crystalline form ofthe compound{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamideaccording to claim
 2. 15. The method according to claim 14, wherein themethod is for the treatment of a disorder selected from the groupconsisting of chronic kidney disease (CKD), diabetes, diabeticnephropathy, diabetic retinopathy, diabetic vasculopathy, chronic heartfailure and diastolic dysfunction.
 16. The method according to claim 14,wherein the method is for the treatment of a disorder selected from thegroup consisting of hypertension, pulmonary hypertension, diabeticarteriopathy, heart failure, erectile dysfunction, angina pectoris andchronic kidney disease.
 17. The method according to claim 14, whereinthe method is for the treatment of a disease selected from the groupconsisting of essential hypertension, resistant hypertension, pulmonaryhypertension and pulmonary arterial hypertension.